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Abstracts

Cancer: Gene Therapies, Stem Cells, Telomeres, and Cytokines
Updated: 08/26/2004

ABSTRACTS

U.S. Research: Find How Key Anti-Cancer Gene Works.

Anon.

1997

Physiology of cytokine pathways in rheumatoid arthritis.

Arend WP.

Arthritis Rheum. 2001 Feb; 45(1):101-6.

This review has summarized the physiology of some cytokine pathways in RA, emphasizing the redundant and synergistic nature of this network. However, it is important to understand that this system is self-regulating through the action of anti-inflammatory cytokines, opposing cytokines, cytokine receptor antagonists, and possibly naturally occurring antibodies to cytokines (Figure 1). Disease results when an imbalance in the cytokine network develops, either from excess production of pro-inflammatory cytokines or from inadequate presence of natural anti-inflammatory mechanisms. The current therapeutic approaches to RA that are aimed at restoring this balance include the use of monoclonal antibodies to TNFalpha, soluble TNFalpha receptors, and IL-1Ra. Other therapeutic agents that interfere with the cytokine network are in various stages of preclinical and clinical evaluation

Resveratrol-induced inactivation of human gastric adenocarcinoma cells through a protein kinase C-mediated mechanism.

Atten MJ, Attar BM, Milson T, et al.

Biochem Pharmacol. 2001 Nov 15; 62(10):1423-32.

Resveratrol, a polyphenolic phytochemical present in berries, grapes, and wine, has emerged as a promising chemopreventive candidate. Because there is scant information regarding natural agents that prevent, suppress, or reverse gastric carcinogenesis, the aim of the present study was to determine the chemopreventive potential of resveratrol against gastric cancer by investigating cellular and molecular events associated with resveratrol treatment of human gastric adenocarcinoma cells. We determined the action of resveratrol on cellular function and cellular integrity by measuring DNA synthesis, cellular proliferation, cell cycle distribution, cytolysis, apoptosis, and phosphotransferase activities of two key signaling enzymes, protein kinase C (PKC) and mitogen-activated protein kinases (ERK1/ERK2), in human gastric adenocarcinoma KATO-III and RF-1 cells. Resveratrol inhibited [3H]thymidine incorporation into cellular DNA of normally proliferating KATO-III cells and of RF-1 cells whose proliferation was stimulated with carcinogenic nitrosamines. Treatment with resveratrol arrested KATO-III cells in the G(0)/G(1) phase of the cell cycle and eventually induced apoptotic cell death, but had a minimal effect on cell lysis. Resveratrol treatment had no effect on ERK1/ERK2 activity but significantly inhibited PKC activity of KATO-III cells and of human recombinant PKCalpha. Results indicate that resveratrol has potential as a chemopreventive agent against gastric cancer because it exerts an overall deactivating effect on human gastric adenocarcinoma cells. Resveratrol-induced inhibition of PKC activity and of PKCalpha, without any change in ERK1/ERK2 activity, suggests that resveratrol utilizes a PKC-mediated mechanism to deactivate gastric adenocarcinoma cells

Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia.

Bechter OE, Eisterer W, Pall G, et al.

Cancer Res. 1998 Nov 1; 58(21):4918-22.

The telomere-telomerase hypothesis states that the vast majority of human tumors have a prolonged replicative life span throughout expressing telomerase, which compensates the cell division-associated loss of telomere DNA. The use of telomere length and telomerase expression as new biological markers in cancer patients requires their correlation with disease prognosis. We, therefore, correlated the mean telomere length based on a telomere restriction fragment assay and the activity of telomerase measured with a telomeric repeat amplification protocol with clinical data and overall survival in 58 patients with B cell chronic lymphocytic leukemia (B-CLL). Telomere length showed a highly inverse correlation to telomerase activity. Patients with telomeres below 6.0 kb were associated with high telomerase activity, whereas patients with a telomere length >6.0 kb generally showed low enzyme activity (P <0.001). Patients in Binet A exhibited significantly longer telomeres and had less telomerase activity than did patients in Binet B or Binet C, where significantly shorter telomeres and higher telomerase activity were observed (P=0.031). Short telomere length and high telomerase activity were significantly associated with a shorter median survival (P=0.02 and P <0.001), and telomerase activity was the most significant prognostic factor for overall survival in B-CLL (P <0.001). Our data provide evidence that telomere length, as well telomerase activity, exerts a strong impact on the survival of B-CLL patients and that telomerase activity can be used as a new prognostic marker in this disease

Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer.

Belluco C, Nitti D, Frantz M, et al.

Ann Surg Oncol. 2000 Mar; 7(2):133-8.

BACKGROUND: Interleukin-6 (IL-6) is an important proinflammatory cytokine that has multiple effects on stimulating inflammation and cell growth. Experimental data suggest that carcinoembryonic antigen (CEA) induces the systemic production of IL-6 and that IL-6 may stimulate tumor cell growth at metastatic sites. We tested the hypothesis that blood concentrations of IL-6 are associated with the amount of circulating CEA and with prognosis in patients with colorectal cancer. METHODS: CEA and IL-6 concentrations were measured by using enzyme immunoassay in preoperative serum samples from 208 patients with stages I through IV colorectal cancer. RESULTS: Linear regression analysis showed a significant association between serum values of CEA and IL-6 (r = .544; R2 = .296; P < .001). Patients with stage III and stage IV disease had a significantly higher IL-6 serum concentration than those with stage I and stage II disease. In patients with stages I through III, 5-year survival was 83% in cases with concentrations of IL-6 at 10 pg/ml or less (n = 94) and 56% in cases with IL-6 concentrations of more than 10 pg/ml (n = 54; P = .001; median follow-up time, 46 months). By using multivariate analysis, an IL-6 concentration of more than 10 pg/ml was an independent prognostic factor of survival (relative risk = 1.820; P = .020). CONCLUSIONS: In patients with colorectal cancer, blood concentration of IL-6 is associated with high circulating CEA and advanced stage. Furthermore, an IL-6 concentration of more than 10 pg/ml is an independent negative prognostic marker of survival

Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients.

Benoy I, Salgado R, Colpaert C, et al.

Clin Breast Cancer. 2002 Jan; 2(4):311-5.

Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF

Interleukin 6 and tumour necrosis factor alpha serum levels in monoclonal gammopathy of undetermined significance.

Blade J, Filella X, Montoto S, et al.

Br J Haematol. 2002 May; 117(2):387-9.

The objectives of the present study were to compare the interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) serum levels of individuals with monoclonal gammopathy of undetermined significance (MGUS) with those of healthy controls, and to ascertain the predictor value of these cytokines in the evolution from MGUS to multiple myeloma. After a median follow-up of 7 years from the initial cytokine measurements, nine patients with MGUS have evolved to a malignant condition. The actuarial probability of malignant transformation in patients with increased IL-6 and TNF-alpha was not significantly higher than in those with normal values

Antioxidants inhibit cytokine production and suppress NF-kappaB activation in CAPAN-1 and CAPAN-2 cell lines.

Blanchard JA, Barve S, Joshi-Barve S, et al.

Dig Dis Sci. 2001 Dec; 46(12):2768-72.

Interleukin (IL) -6 and IL-8 are cytokines that have been shown to play a role in several pancreatic diseases, including acute pancreatitis, chronic pancreatitis, and pancreatic adenocarcinoma. Previously, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) and gram-negative bacterial lipopolysaccharide stimulate production of IL-6 and IL-8 and activation of the transcription factor NF-kappaB in the well-differentiated pancreatic ductal adenocarcinoma cell lines CAPAN-1 and CAPAN-2. In these studies we have examined the effect of chain-breaking and glutathione-enhancing antioxidants on NF-kappaB activation and production of IL-6 and IL-8 in these cell lines. Generally, suppression of NF-kappaB activation correlated well with inhibition of IL-6 and IL-8 secretion. In the CAPAN-2 cell line, antioxidants inhibited both NF-kappaB activation and IL-6 and IL-8 secretion. In the CAPAN-1 cell line, antioxidants generally failed to suppress both NF-kappaB activation and IL-6 and IL-8 secretion. The single exception was the chain-breaking antioxidant butylated hydroxyanisole (BHA), which markedly inhibited IL-6 and IL-8 secretion, but had no effect on NF-kappaB activation. These findings may have implications for the treatment of acute and chronic pancreatitis and pancreatic cancer

CTR95: Adjuvant Nutrition in Cancer Treatment: Laying the Foundation (tapes available from Conference Recording Service, (510) 527-3600).

Bland J.

7777;none;

Farnesyl transferase inhibitors. Presented at Comprehensive Cancer Care.

Bland J.

2001;October 17-21, 2001;

A prospective trial of midwest breast cancer patients: a p53 gene mutation is the most important predictor of adverse outcome.

Blaszyk H, Hartmann A, Cunningham JM, et al.

Int J Cancer. 2000 Jan 20; 89(1):32-8.

Several retrospective studies have suggested p53 gene mutation as an adverse prognostic indicator in breast cancer patients, based on a selective growth advantage of p53 mutant cancer cells and their presumed resistance to current adjuvant therapy regimens. A cohort of 90 Caucasian midwestern breast cancer patients was analyzed prospectively (60 months of follow-up) with a rigorous mutation detection methodology. The presence of a p53 gene mutation was the single most adverse prognostic indicator for recurrence (p = 0.0032) and death (p = 0.0001), and was associated with poor response to both adjuvant (p = 0.0001) and palliative (p = 0.006) therapy. Analysis of the p53 gene with appropriate mutation detection methodology markedly improves the prediction of early recurrence, treatment failure, and death in breast cancer patients

Extension of life-span by introduction of telomerase into normal human cells.

Bodnar AG, Ouellette M, Frolkis M, et al.

Science. 1998 Jan 16; 279(5349):349-52.

Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine

Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase.

Bowie AG, O'Neill LA.

J Immunol. 2000 Dec 15; 165(12):7180-8.

The transcription factor NF-kappaB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-kappaB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-kappaB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-kappaB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-kappaB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-kappaBalpha (inhibitory protein that dissociates from NF-kappaB), due to inhibition of I-kappaB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-kappaBalpha phosphorylation, and NF-kappaB activation. The results identify p38 as an intracellular target for high dose vitamin C

Antioxidants may limit key mutations.

Brotzman M.

ScienceNewsOnline. 1999; 155(17)

Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines.

Bu SZ, Yin DL, Ren XH, et al.

Cancer. 1997 May 15; 79(10):1944-50.

BACKGROUND: Progesterone (PROG) has been shown to reduce the risk of developing ovarian carcinoma in postmenopausal women who have undergone estrogen and progestogen replacement therapy, and it has been clinically used to treat some types of ovarian tumors. It is not yet clear whether or not the antitumor activity of progestogen is due to its ability to induce apoptosis in precarcinomatous and carcinomatous ovarian cells. The apoptosis-related genes p53, bcl-2, and c-myc have important roles in the regulation of programmed cell death, and thus may be involved in the process of the suspected PROG-induced apoptosis. METHODS: Antiproliferation effects of PROG on 3AO and AO ovarian carcinoma cells were determined by 3H-thymidine incorporation. Apoptosis of the PROG-treated cells was determined by DNA laddering analysis and was quantitated by both nuclear condensation and flow cytometry after cells were stained with propidium iodide. Cell cycle analysis was also performed by flow cytometry. The expression of p53, bcl-2, and c-myc after 72 hours of PROG treatment was detected by Northern blot analysis. RESULTS: In both 3AO and AO cell lines, cells proliferation was maximally inhibited by PROG after 72 hours of treatment at 10 microM concentration. Under the same conditions, more than 50% of PROG-treated cells had undergone apoptosis, whereas less than 3% of the cells were apoptotic in untreated cell cultures. After exposure to PROG for 72 hours, cells were arrested in the G1 phase of the cell cycle, and the levels of p53 mRNA were remarkably increased in both cell lines. No changes in expression of bcl-2 or c-myc were detected. CONCLUSIONS: PROG significantly inhibited cell proliferation and induced apoptosis in both of the ovarian carcinoma cell lines tested in this study. PROG treatment markedly up-regulated p53 expression in these cells, indicating involvement of p53 in PROG-induced apoptosis

p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study.

Buttitta F, Marchetti A, Gadducci A, et al.

Br J Cancer. 1997; 75(2):230-5.

Chemotherapeutic management of ovarian cancers is a difficult task as these neoplasms show significant differences in chemosensitivity, even if they share identical clinicopathological features. The present study was undertaken to investigate the prognostic and predictive role of p53 alterations in ovarian cancer. To this end, using different technical approaches, i.e. genetic and immunohistochemical analyses, we analysed a series of 68 ovarian neoplasms including 15 low malignant potential (LMP) tumours and 53 invasive carcinomas. We never observed p53 abnormalities in LMP tumours. p53 alterations were present only in invasive ovarian carcinomas, and they were detected much more frequently in tumours characterized by high histological grade (P = 0.01) and advanced-stage disease (P = 0.006 and P = 0.05 for gene mutations and protein expression respectively). For 33 patients with invasive ovarian cancer, information was available concerning response to cisplatin-based chemotherapy. A strong correlation (P = 0.001) has emerged between p53 alterations and response to chemotherapy; only one (14%) of seven patients who had a pathological complete response to antiblastic drugs showed p53 aberrations, whereas 18 (82%) of 22 cases with partial response and all of the four non-responsive patients scored positive for p53 abnormalities. We also observed that patients with p53 mutations had a significantly shorter progression-free survival than patients with p53-negative tumours (P = 0.05). Taken together, our results strongly suggest that in epithelial ovarian malignancies tumours showing p53 aberrations are significantly less sensitive to chemotherapy and more aggressive than those with functional p53. Thus, a routine analysis of this gene could have profound implications for the treatment of ovarian cancer

Geron and Rpi form collaboration in telomerase inhibition.

BW.

Business Wire. 2001;

Design of telomerase inhibitors for the treatment of cancer.

Cairns D, Anderson RJ, Perry PJ, et al.

Curr Pharm Des. 2002; 8(27):2491-504.

Telomerase is a cellular ribonucleoprotein reverse transcriptase responsible for the maintenance of telomeres, the tandemly repeating guanine-rich nucleic acid sequences at the 3'-ends of eukaryotic chromosomes that serve to protect chromosomal stability and maintain integrity. Telomerase enzyme activity is essential for the sustained proliferation of most immortal cells, including cancer cells, and is currently an important recognised target for the development of novel and potentially tumour-specific anticancer chemotherapeutics. Herein, we review recent advances in the design and development of telomerase inhibitors for the treatment of cancer. To date, these have included antisense strategies, reverse transcriptase inhibitors, and agents capable of interacting with high-order telomeric DNA tetraplex (or "G-quadruplex") structures in such a way as to prevent enzyme access to its required linear telomeric DNA substrate. Critical appraisal of each distinct approach is provided together with highlighted areas for continued development necessary to further refine the present disparate classes of telomerase inhibitors for use in clinically viable therapies

[Interleukins and inflammation].

Cavaillon JM.

Pathol Biol (Paris). 1990 Jan; 38(1):36-42.

Interleukins (IL) are a heterogeneous class of cytokines involved in activation of T lymphocytes (IL-1, 2, 4, 6 and 7), B lymphocytes (IL-1, 2, 4, 5, 6 and 7), and macrophages (IL-1 and 4), and hematopoiesis (IL-1, 2, 3, 4, 5, 6 and 7), acting either by themselves, or as co-stimulator factors. Interleukin-1 (IL-1 alpha and IL-1 beta) is induced by different signals including microbial products; it mediates various events occurring during inflammation (e.g. fever, osteolysis, leucopenia, hypotension, hyperalgia, etc...). Such mechanisms are often the consequences of the induction by IL-1 of lipid mediators (e.g. prostaglandins, platelet activating factor, etc). IL-1 often acts synergistically with Tumor Necrosis Factor during the pro-inflammatory process. IL-1 as well as microbial products induces the production of interleukin-6 and interleukin-8. IL-6 also plays a role in inflammation, mainly as an inducer of acute phase proteins synthesis by hepatocytes. IL-8 has chemotactic and activating properties for neutrophils

Use of Umbilical Cord Blood Expands Option of Transplantation to More Children.

Chalaire D.

2000

Natural remedies for inflammation.

Challem J.

Let's Live Magazine 2000. 2000

Mechanisms of p53-induced apoptosis: in search of genes which are regulated during p53-mediated cell death.

Choisy-Rossi C, Reisdorf P, Yonish-Rouach E.

Toxicol Lett. 1998 Dec 28; 102-103:491-6.

The tumor suppressor gene p53 is a major player in the protection of cells from DNA damage. In the majority of human cancers, p53 is functionally inactivated--mostly by mutations but also by interaction with viral or cellular proteins. Wild-type p53 is involved in essential functions such as DNA repair, transcription, genomic stability, senescence, cell cycle control and apoptosis. It was shown to be a sequence-specific transcriptional activator, and this activity appears to be necessary to impose growth arrest. A major target gene which participates in p53-mediated growth arrest is p21/Waf1, an inhibitor of cyclin-dependent kinases. Whether or not transcriptional activation of target genes is required for p53-mediated apoptosis may depend on the cell type and external factors, and the mechanism of cell death induction is not clear yet. We have employed clones of the M1 myeloid leukemic cell line expressing a temperature-sensitive p53 mutant to study genes which are regulated during p53-induced apoptosis

Cytokines in Cancer.

CIC.

2000

Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues.

Cushman M, Nagarathnam D, Burg DL, et al.

J Med Chem. 1991 Feb; 34(2):798-806.

Treatment of o-hydroxyacetophenones 2a-e with excess lithium bis(trimethylsilyl)amide followed by dialkyl carbonates gave alkyl 3-(2-hydroxyaryl)-3-oxopropanoates 3a-e. The latter substances were transformed through the reaction of their magnesium chelates with benzoyl chlorides into a series of 3-(alkoxycarbonyl)-2-arylflavones, which were subsequently elaborated into a variety of flavonoids. These compounds were tested for their abilities to inhibit the in vitro protein-tyrosine kinase activity of p56lck, an enzyme which is thought to play a key role in mediating signal transduction from the CD4 receptor during lymphocyte activation. All of the active compounds had either an amino or a hydroxyl substituent at the 4'-position of the 2-aryl ring. The most active substance prepared in this study is compound 17c, which is approximately 1 order of magnitude more potent than the natural product quercetin (1). Compound 17c was a competitive inhibitor of p56lck with respect to ATP and was highly selective for the inhibition of protein-tyrosine over protein-serine/threonine kinases

Pathfinder Encyclopedia.

Cytokines Online 2002.

Cytokines Online 2002. 2002

Differential regulation of IL-13 and IL-4 production by human CD8+ and CD4+ Th0, Th1 and Th2 T cell clones and EBV-transformed B cells.

de Waal MR, Abrams JS, Zurawski SM, et al.

Int Immunol. 1995 Sep; 7(9):1405-16.

In the present study, the requirements and characteristics for the production of IL-13 by human T cells, T cell clones and B cells were determined and compared with those of IL-4. IL-13 was produced by human CD4+ and CD8+ T lymphocyte subsets isolated from peripheral blood mononuclear cells and by CD4+ and CD8+ T cell clones. CD4+ T cell clones belonging to Th0, Th1-like and Th2-like subsets produced IL-13 following antigen-specific or polyclonal activation. In addition, EBV-transformed B cell lines expressed IL-13 mRNA and produced small amounts of IL-13 protein. Expression of IL-13 mRNA and production of IL-13 protein by peripheral blood T cells and T cell clones was induced rapidly and was relatively long lasting, whereas IL-4 production by these cells was transient. In addition, IL-13 mRNA expression was induced by modes of activation that failed to induce IL-4 mRNA expression. IL-13 shares many biological activities with IL-4 which is compatible with the notion that the IL-13 and IL-4 receptors share a common component required for signal transduction. However, IL-13 lacks the T cell-activating properties of IL-4. Here we have shown that this is related to the fact that T cells fail to bind radiolabeled IL-13 and do not express the IL-13-specific receptor component. Taken together, these results indicate that the differences in expression and biological activities of IL-4 and IL-13 on T cells may have consequences for the relative roles of these cytokines in the immune response

Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients.

Devaraj S, Jialal I.

Free Radic Biol Med. 2000 Oct 15; 29(8):790-2.

Type 2 diabetic subjects have an increased propensity to premature atherosclerosis. Alpha tocopherol (AT), a potent antioxidant, has several anti-atherogenic effects. There is scanty data on AT supplementation on inflammation in Type 2 diabetic subjects. The aim of the study was to test the effect of RRR-AT supplementation (1200 IU/d) on plasma C-reactive protein (CRP) and interleukin-6 (IL-6) release from activated monocyte in Type 2 diabetic patients with and without macrovascular complications compared to matched controls. The volunteers comprised Type 2 diabetic subjects with macrovascular disease (DM2-MV, n = 23), Type 2 diabetic subjects without macrovascular complications (DM2, n = 24), and matched controls (C, n = 25). Plasma high sensitive CRP (Hs-CRP) and Monocyte IL-6 were assayed at baseline, following 3 months of supplementation and following a 2 month washout phase. DM2-MV subjects have elevated HsCRP and monocyte IL-6 compared to controls. AT supplementation significantly lowered levels of C-reactive protein and monocyte interleukin-6 in all three groups. In conclusion, AT therapy decreases inflammation in diabetic patients and controls and could be an adjunctive therapy in the prevention of atherosclerosis

Expression of TNF-alpha by human plasma cells in chronic inflammation.

Di Girolamo N, Visvanathan K, Lloyd A, et al.

J Leukoc Biol. 1997 Jun; 61(6):667-78.

Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine and mediator of the inflammatory response. It has been implicated in the pathogenesis of many inflammatory disorders, including rheumatoid arthritis (RA), septic shock, and Crohn's disease. Using a specific anti-human TNF-alpha antibody we detected immunoreactivity for this cytokine in the cytoplasm of inflammatory cells in several chronic inflammatory disorders, including RA, scleritis, and polyarteritis nodosa. These cells were identified predominantly as IgG-expressing plasma cells. Lymph nodes from patients with Hodgkin's lymphoma and breast cancer, but not from control subjects, were also found to contain TNF-alpha-positive plasma cells. Cultured EBV-B lymphocytes and a human plasma cell line (ARH-77) when stimulated with phorbol myristate acetate demonstrated cytoplasmic TNF-alpha immunoreactivity. Western blot analysis of cell membranes and conditioned media from both cell types revealed the presence of the 26-kDa membrane-bound from and the 17-kDa soluble from of TNF-alpha, respectively. TNF-alpha was quantitated by enzyme-linked immunosorbent assay and found to be biologically active as determined by the L929 cytotoxicity assay. This is the first demonstration that plasma cells may be capable of modulating immune and inflammatory responses, not only by antibody production, but also by their secretion of a key inflammatory mediator, TNF-alpha

Role of pro- and anti-inflammatory cytokines during inflammation: experimental and clinical findings.

Dinarello CA.

J Biol Regul Homeost Agents. 1997 Jul; 11(3):91-103.

There is an emerging concept that the net biological response of pro and anti-inflammatory cytokines affects the outcome of certain diseases. In inflammatory diseases, interleukin-1 (IL-1) and tumor necrosis factor (TNF) are produced and function primarily as pro-inflammatory cytokines. In addition, other cytokines such as IFN gamma, IL-12 and IL-18 are also produced and affect the production and cellular response to IL-1 and TNF. Biologically, IL-1 and TNF are closely related, although the respective structures and the specific receptors for IL-1 and TNF are clearly distinct. IL-1 and TNF are truly pleiotropic cytokines and are active in the low pM and fM range. Because of their multiple pro-inflammatory properties, these cytokines contribute to disease. Most of our knowledge on IL-1 and TNF are derived from experiments in which either humans or animals have been injected with the cytokine or added to cells in vitro. However, in models of inflammation where several cytokines are produced, specific blockade of either IL-1 or TNF or both results is a reduction in the severity of the inflammation. These latter data therefore implicate IL-1 and TNF as primary cytokines involved with inflammation. Moreover, IL-1 and TNF act synergistically in nearly every in vitro and in vivo model of inflammation. This review will focus on IL-1 and TNF as cytokines of strategic importance to the initiation and progression of inflammation. In addition, this review examines the effects of anti-inflammatory cytokines which non-specifically reduce the production and activity of IL-1 and TNF

How cancer cells cheat death.

DiS.

Daily InScight 1997. 1997

Evaluation of interleukin-6 in bronchoalveolar lavage fluid and serum of patients with lung cancer.

Dowlati A, Levitan N, Remick SC.

J Lab Clin Med. 1999 Oct; 134(4):405-9.

Increased levels of serum interleukin 6 (IL-6) are found in patients with lung cancer, and it has been shown that this is part of a systemic inflammatory response syndrome. This study was designed to measure IL-6 levels in bronchoalveolar lavage (BAL) fluid of patients with lung cancer and to describe the relationship of BAL fluid IL-6 to the known systemic increase in IL-6. Increased levels of BAL fluid IL-6 can be found in patients with lung cancer as compared with patients with chronic obstructive pulmonary disease who have acute infection (P = .007). In patients with cancer, no correlation between BAL fluid IL-6 and serum IL-6 was found (P = .8). BAL fluid IL-6 did not correlate with the number of lymphocytes or macrophages found in this fluid. BAL fluid IL-6 does not correlate with tumor size. Although serum IL-6 was higher in patients with extensive stage small cell lung cancer as compared with levels in patients with limited stage disease (P = .06), their corresponding BAL fluid levels were not different (P = .9). Serum IL-6 correlated with other acute phase reactants. This study thus demonstrates the feasibility of utilizing BAL fluid analysis for local cytokine/tumor marker production in lung carcinoma. It also shows that a local increase in IL-6 in the BAL fluid is independent of the systemic inflammatory response syndrome, whereas the serum increase in IL-6 is part of this syndrome

TNFalpha-induced suppression of PMN apoptosis is mediated through interleukin-8 production.

Dunican AL, Leuenroth SJ, Grutkoski P, et al.

Shock. 2000 Sep; 14(3):284-8.

Dysregulated neutrophil (polymorphonuclear PMN) apoptosis is thought to contribute to the onset of adult respiratory distress syndrome (ARDS) in critically ill patients. Tumor necrosis factor-alpha (TNFalpha), which is present in elevated levels in the bronchoalveolar lavage fluid in patients with ARDS, is thought to play a central role in regulating PMN function in the lungs. Studies have shown that short-term culture with TNFalpha increases apoptosis yet extended culture with TNFalpha suppresses apoptosis. However, it is unclear whether this latter effect of TNFalpha is directly or indirectly mediated through production of anti-apoptotic cytokines such as interleukin (IL)-8. To investigate the role of IL-8 in TNFalpha-induced apoptosis PMN were exposed to TNFalpha (100 ng/mL) in the presence or absence of antibodies to IL-8, and the extent of apoptosis was assessed. An enzyme-linked immunoassay was used to measure levels of the anti-apoptotic cytokine IL-8, induced by TNFalpha-stimulation. Because TNFalpha may mediate its effect through various cell-signaling pathways, we next assessed the effect of kinase inhibition on the ability of TNFalpha to effect apoptosis and IL-8 production. Treatment with TNFalpha had a biphasic effect: at 4-8 h, apoptosis was increased but was markedly suppressed at 24 h (P < 0.05). PMN cultured for 24 h with TNFalpha also showed markedly increased levels of IL-8. Neutralization of IL-8 inhibited the ability of TNFalpha to suppress apoptosis (P < 0.05). Incubation of TNFalpha + p38-mitogen-activated protein kinase (MAPK) inhibitor SB202190 increased apoptosis (P < 0.01) and decreased IL-8 production to PMN control. To a lesser extent, incubation of TNFalpha with inhibitors to NF-kappaB (SN50) and PI3K (LY294002) also increased apoptosis and decreased IL-8 production (P < 0.05). These data illustrate a novel mechanism by which TNFalpha can indirectly elicit an anti-apoptotic effect via p38-MAPK induced release of the anti-apoptotic chemokine IL-8. The exploitation of such a pathway represents a potential target for regulation of PMN-mediated acute lung injury

alpha-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-kappa B mobilization.

Erl W, Weber C, Wardemann C, et al.

Am J Physiol. 1997 Aug; 273(2 Pt 2):H634-H640.

The adherence of monocytes to activated endothelium is an early event in atherogenesis. Because antioxidants have been considered to be of antiatherosclerotic potential, we investigated the effects of alpha-tocopherol (TCP) and its acetate and succinate esters on monocyte adhesion to cytokine-stimulated human umbilical vein endothelial cells (HUVEC). Endothelial cells were treated with TCP, alpha-tocopherol acetate (TCP acetate), or alpha-tocopheryl succinate (TCP succinate) before stimulation with tumor necrosis factor-alpha (TNF-alpha; 10 U/ml, 6 h) or interleukin-1 beta (IL-1 beta; 10 U/ml, 6 h). Cytokine-stimulated cell surface expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (ELAM-1, CD62E), but not of intercellular adhesion molecule-1 (ICAM-1, CD54), was time- and dose-dependently inhibited by TCP succinate but not by TCP or TCP acetate. TCP succinate (200 microM, 24 h) reduced TNF-induced VCAM-1 and E-selectin expression from a specific mean fluorescence intensity of 151 +/- 28 to 12 +/- 4 channels and from 225 +/- 38 to 79 +/- 21 channels, respectively. Succinate alone had no effect. Decreased adhesion molecule expression was associated with a reduction of monocytic cell adhesion. TCP succinate (20 microM, 72 h), but not TCP (200 microM, 72 h), reduced U-937 cell adhesion to TNF-alpha-stimulated (10 U/ml, 6 h) HUVEC by 30% (P < 0.025) and to IL-1 beta-stimulated HUVEC by 56% (P < 0.010). Electrophoretic mobility-shift assays of HUVEC nuclear proteins revealed a decrease in TNF-alpha-stimulated nuclear factor-kappa B (NF-kappa B) activation after pretreatment of HUVEC with TCP succinate but not with TCP, TCP acetate, or succinate alone. In conclusion, we demonstrate that the vitamin E derivative TCP succinate prevents monocytic cell adhesion to cytokine-stimulated endothelial cells by inhibiting the activation of NF-kappa B, further emphasizing the antiatherosclerotic potential of lipid soluble antioxidants

Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome.

Fayad L, Keating MJ, Reuben JM, et al.

Blood. 2001 Jan 1; 97(1):256-63.

The objective of this study was to examine the correlation between serum interleukin-6 (IL-6) and IL-10 levels and outcome in chronic lymphocytic leukemia (CLL). Serum IL-6 and IL-10 levels were measured by enzyme-linked immunoabsorbent assays from 159 and 151 CLL patients, respectively, and from healthy control subjects (n = 55 [IL-6]; n = 37 [IL-10]). Cytokine levels were correlated with clinical features and survival. Serum IL-6 levels were higher in CLL patients (median, 1.45 pg/mL; range, undetectable to 110 pg/mL) than in control subjects (median, undetectable; range, undetectable to 4. 30 pg/mL) (P <.0001). Serum IL-10 levels were higher in CLL patients (median, 5.04 pg/mL; range, undetectable to 74 pg/mL) than in normal volunteers (median, undetectable; range, undetectable to 13.68 pg/mL) (P <.00001). Assays measuring both Epstein-Barr virus-derived and human IL-10 yielded higher values than assays measuring primarily human IL-10 (P <.05). Patients with elevation of serum IL-6 or IL-10 levels, or both, had worse median and 3-year survival (log rank P <.001) and unfavorable characteristics (prior treatment, elevated beta(2)-microglobulin or lactate dehydrogenase, or Rai stage III or IV). Elevated IL-6 and IL-10 levels were independent prognostic factors for survival when analyzed individually or in combination (Cox regression analysis). However, if beta(2)-microglobulin was incorporated into the analysis, it was selected as an independent prognostic feature, and IL-6/IL-10 were no longer selected. In patients with CLL, serum IL-6 and IL-10 (viral and human) levels are elevated and correlate with adverse disease features and short survival. In multivariate analysis, however, beta(2)-microglobulin is the most important prognostic factor

The price of tumour suppression?

Ferbeyre G, Lowe SW.

Nature. 2002 Jan 3; 415(6867):26-7.

Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo.

Frater-Schroder M, Risau W, Hallmann R, et al.

Proc Natl Acad Sci U S A. 1987 Aug; 84(15):5277-81.

Tumor necrosis factor type alpha (TNF-alpha) inhibits endothelial cell proliferation in vitro. Basal cell growth (in the absence of exogenously added growth factor) and fibroblast growth factor (FGF)-stimulated cell proliferation are inhibited in a dose-dependent manner from 0.1 to 10 ng/ml with half-maximal inhibition occurring at 0.5-1.0 ng of TNF-alpha per ml. Bovine aortic and brain capillary endothelial and smooth muscle cells are similarly affected. TNF-alpha is a noncompetitive antagonist of FGF-stimulated cell proliferation. Its action on endothelial cells is reversible and noncytotoxic. Surprisingly, TNF-alpha does not seem to inhibit endothelial cell proliferation in vivo. In the rabbit cornea, even a high dose of TNF-alpha (10 micrograms) does not suppress angiogenesis induced by basic FGF. On the contrary, in this model system TNF-alpha stimulates neovascularization. The inflammatory response that is seen in the cornea after TNF-alpha implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration

Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways.

Fujita J, Tsujinaka T, Yano M, et al.

Int J Cancer. 1996 Nov 27; 68(5):637-43.

Progression of skeletal muscle atrophy is one of the characteristic features in cancer patients. Interleukin-6 (IL-6) has been reported to be responsible for the loss of lean body mass during cancer cachexia in colon-26 adenocarcinoma (C-26)-bearing mice. This study was carried out to elucidate the intracellular proteolytic pathways operating in skeletal muscle in C-26-bearing mice, and to examine the effect of anti IL-6 receptor antibody on muscle atrophy. On day 17 after tumor inoculation, the gastrocnemius muscle weight of C-26-bearing mice had significantly decreased to 69% of that of the pair-fed control mice. This weight loss occurred in association with increases in the mRNA levels of cathepsins B and L, poly-ubiquitin (Ub) and the subunits of proteasomes in the muscles. Furthermore, enzymatic activity of cathepsin B+L in the muscles also increased to 119% of the control. The administration of anti-murine IL-6 receptor antibody to C-26-bearing mice reduced the weight loss of the gastrocnemius muscles to 84% of that of the control mice, whose enzymatic activity of cathepsin B+L and mRNA levels of cathepsin L and poly-Ub were significantly suppressed compared with those of the C-26-bearing mice. Our data indicate that both the lysosomal cathepsin pathway and the ATP-dependent proteolytic pathway might be involved in the muscle atrophy of C-26-bearing mice. The results also suggest that anti IL-6 receptor antibody could be a potential therapeutic agent against muscle atrophy in cancer cachexia by inhibiting these proteolytic systems

Human prostatic carcinoma cells produce an increase in the synthesis of interleukin-6 by human osteoblasts.

Garcia-Moreno C, Mendez-Davila C, de La PC, et al.

Prostate. 2002 Mar 1; 50(4):241-6.

BACKGROUND: The aim of this work was to evaluate the effect produced by conditioned medium from human prostatic carcinoma cell (PC-3) culture on human osteoblast (HOB) interleukin 6 (IL-6) synthesis. METHODS: PC-3 cells were cultured in Ham's F12K medium with 10% fetal calf serum (FCS) up to confluence. Medium was changed by Dulbecco modified Eagle medium (DMEM)/F12K (1:1) with 0.1% bovine serum albumin. Cells were cultured for 24 hr, and medium (PC-3-CM) was collected. HOBs were cultured up to confluence, and after 48 hr without FCS, medium was removed and PC-3-CM was added to the wells. After 24 hr, supernatant was collected for the determination of IL-6. In another experiment, HOBs were cultured up to confluence in Petri dishes, and after 48 hr without FCS, PC-3-CM or DMEM/F12K (1:1) was added. After different periods of time, medium was removed, and total RNA was extracted. IL-6 mRNA was quantified using reverse transcription polymerase chain reaction. RESULTS: PC-3-CM significantly enhanced IL-6 secretion into HOB culture supernatants (between 1,812% and 372%, depending on the osteoblastic line) with respect to HOBs cultured in DMEM/F12K. PC-3-CM also produced an increase in IL-6 mRNA levels in HOBs. CONCLUSIONS: Prostate carcinoma cells (PC-3) produce a factor or factors that enhance the synthesis and release of IL-6, a known activator of bone resorption

Protein kinase C signaling and oxidative stress.

Gopalakrishna R, Jaken S.

Free Radic Biol Med. 2000 May 1; 28(9):1349-61.

Oxidative stress is involved in the pathogenesis of various degenerative diseases including cancer. It is now recognized that low levels of oxidants can modify cell-signaling proteins and that these modifications have functional consequences. Identifying the target proteins for redox modification is key to understanding how oxidants mediate pathological processes such as tumor promotion. These proteins are also likely to be important targets for chemopreventive antioxidants, which are known to block signaling induced by oxidants and to induce their own actions. Various antioxidant preventive agents also inhibit PKC-dependent cellular responses. Therefore, PKC is a logical candidate for redox modification by oxidants and antioxidants that may in part determine their cancer-promoting and anticancer activities, respectively. PKCs contain unique structural features that are susceptible to oxidative modification. The N-terminal regulatory domain contains zinc-binding, cysteine-rich motifs that are readily oxidized by peroxide. When oxidized, the autoinhibitory function of the regulatory domain is compromised and, consequently, cellular PKC activity is stimulated. The C-terminal catalytic domain contains several reactive cysteines that are targets for various chemopreventive antioxidants such as selenocompounds, polyphenolic agents such as curcumin, and vitamin E analogues. Modification of these cysteines decreases cellular PKC activity. Thus the two domains of PKC respond differently to two different type of agents: oxidants selectively react with the regulatory domain, stimulate cellular PKC, and signal for tumor promotion and cell growth. In contrast, antioxidant chemopreventive agents react with the catalytic domain, inhibit cellular PKC activity, and thus interfere with the action of tumor promoters

Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages.

Gosset P, Wallaert B, Tonnel AB, et al.

Eur Respir J. 1999 Jul; 14(1):98-105.

Reactive oxygen intermediates exert signalling functions and modulate gene transcription, particularly for pro-inflammatory cytokines. Since exogenous as well as endogenous thiols could be potent inhibitors of the production of cytokines, the effects of N-acetylcysteine (NAC), glutathione (GSH) and modulated GSH synthesis on the production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 by human alveolar macrophages (AMs) was evaluated, as well as the potential role of intracellular GSH depletion on the effect of exogenous thiols. AMs were stimulated with lipopolysaccharide (LPS) and cytokine production was measured by evaluating messenger ribonucleic acid (mRNA) expression and protein secretion. Depletion of intracellular GSH by treatment with buthionine sulphoximine (BSO) reached 45.2% after 3 h and was nearly complete at 24 h. Whereas a 24-h preincubation of AMs with BSO significantly increased LPS-induced secretion of TNF-alpha and IL-8, a 3-h preincubation only enhanced LPS-stimulated production of IL-8 (p<0.05). Treatment with NAC and GSH did not significantly increase intracellular content of GSH even after a 48-h incubation. Addition of GSH and NAC significantly reduced the secretion of TNF-alpha (mean+/-SEM 21.2+/-5 and 44.7+/-4.4% inhibition, respectively) as well as LPS-induced IL-6 and IL-8 (p<0.05). Similarly, NAC inhibited the production of TNF-alpha, IL-6 and IL-8 in GSH-depleted AMs obtained by BSO pretreatment. In conclusion, N-acetylcysteine and glutathione inhibit the production of tumour necrosis factor-alpha, interleukin-8 and interleukin-6 by alveolar macrophages by a mechanism independent of glutathione metabolism. However, total depletion of glutathione within alveolar macrophages significantly increases tumour necrosis factor-alpha and interleukin-8 synthesis whereas it does not modulate interleukin-6 secretion

Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis.

Greenblatt MS, Bennett WP, Hollstein M, et al.

Cancer Res. 1994 Sep 15; 54(18):4855-78.

Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids.

Grimble RF, Tappia PS.

Z Ernahrungswiss. 1998; 37 Suppl 1:57-65.

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed

Inhibition of telomerase limits the growth of human cancer cells.

Hahn WC, Stewart SA, Brooks MW, et al.

Nat Med. 1999 Oct; 5(10):1164-70.

Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies

Essential involvement of interleukin-8 (IL-8) in acute inflammation.

Harada A, Sekido N, Akahoshi T, et al.

J Leukoc Biol. 1994 Nov; 56(5):559-64.

Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils

Interleukin-10 and its receptor.

Ho AS, Moore KW.

Ther Immunol. 1994 Jun; 1(3):173-85.

The cytokine interleukin-10 (IL-10) has several important activities on cells of the immune system. IL-10 profoundly suppresses activation of macrophages, inhibiting their ability to secrete cytokines and serve as accessory cells for stimulation of T cell and natural killer (NK) cell function. IL-10 also plays a role in stimulating proliferation and differentiation of B cells, mast cells, and both mature and immature T cells. At least two herpesviruses harbor analogs of the IL-10 gene; the Epstein-Barr virus (EBV) homolog (BCRF1, viral IL-10, vIL-10) shares several of the cellular cytokine's activities, one or all of which may be important in the host-virus relationship. This article reviews recent studies on the function of IL-10 and discusses the initial characterization of its receptor

Multiple myeloma: present and future.

Hussein MA, Juturi JV, Lieberman I.

Curr Opin Oncol. 2002 Jan; 14(1):31-5.

Multiple myeloma is a clonal B-cell tumor of slowly proliferating plasma cells within the bone marrow. Among hematologic malignancies, it constitutes 10% of the cancers and ranks as the second most frequently occurring hematologic cancer in the United States, after non-Hodgkin lymphoma. Interleukin-6 is an important cytokine in myeloma cell growth and proliferation. Close cell-to-cell contact between myeloma cells and the bone marrow stromal cells triggers a large amount of interleukin-6 production, which supports the growth of these cells, as well as protecting them from apoptosis induced by dexamethasone and other chemotherapeutic agents. Therapies modulating the tumor and its microenvironment are being actively pursued with the goal of converting multiple myeloma to a chronic disease with the patients maintaining a normal lifestyle

Bioflavonoid quercetin inhibits interleukin-1-induced transcriptional expression of monocyte chemoattractant protein-1 in glomerular cells via suppression of nuclear factor-kappaB.

Ishikawa Y, Sugiyama H, Stylianou E, et al.

J Am Soc Nephrol. 1999 Nov; 10(11):2290-6.

Flavonoids are semiessential food components that possess anti-inflammatory properties. This report describes a novel potential of bioflavonoid quercetin as an inhibitor of monocyte chemoattractant protein-1 (MCP-1) in glomerular cells. Cultured mesangial cells as well as isolated glomeruli expressed MCP-1 mRNA in response to interleukin-1beta (IL-1beta). Quercetin dramatically inhibited the cytokine-triggered MCP-1 expression. To explore the mechanisms involved, effects of quercetin on the putative transcriptional activators of MCP-1, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), were examined. Exposure of the cells to IL-1beta caused activation of NF-kappaB without significant upregulation of AP-1 activity. NF-kappaB inhibitor MG132 diminished the IL-1-induced expression of MCP-1 in mesangial cells and isolated glomeruli, whereas c-Jun/AP-1 inhibitor curcumin did not affect this process. Consistently, NF-kappaB-inactive mesangial cells expressing a super-repressor mutant of IkappaBalpha showed blunted expression of MCP-1 by IL-1beta. In contrast, AP-1-inactive mesangial cells expressing a dominant-negative mutant of c-Jun exhibited the same level of MCP-1 mRNA as that in control cells. These results suggest that: (1) quercetin has the ability to attenuate activation of NF-kappaB; and (2) it inhibits IL-1-triggered MCP-1 expression via suppression of NF-kappaB, but not AP-1, in glomerular cells

Growth Factors and Cytokines.

ISU.

2001

Dietary polyunsaturated fatty acids and inflammatory mediator production.

James MJ, Gibson RA, Cleland LG.

Am J Clin Nutr. 2000 Jan; 71(1 Suppl):343S-8S.

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products

Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity.

Jobin C, Bradham CA, Russo MP, et al.

J Immunol. 1999 Sep 15; 163(6):3474-83.

NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa B activity in some cell types. In this report we investigate the mechanism of action of curcumin on cytokine-induced proinflammatory gene expression using intestinal epithelial cells (IEC). Curcumin inhibited IL-1 beta-mediated ICAM-1 and IL-8 gene expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-kappa B DNA binding activity, RelA nuclear translocation, I kappa B alpha degradation, I kappa B serine 32 phosphorylation, and I kappa B kinase (IKK) activity were blocked by curcumin treatment. Wound-induced p38 phosphorylation was not inhibited by curcumin treatment. In addition, mitogen-activated protein kinase/ERK kinase kinase-1-induced IL-8 gene expression and 12-O-tetraphorbol 12-myristate 13-acetate-responsive element-driven luciferase expression were inhibited by curcumin. However, I kappa B alpha degradation induced by ectopically expressed NF-kappa B-inducing kinase or IKK was not inhibited by curcumin treatment. Therefore, curcumin blocks a signal upstream of NF-kappa B-inducing kinase and IKK. We conclude that curcumin potently inhibits cytokine-mediated NF-kappa B activation by blocking a signal leading to IKK activity

Structural Studies with Protein Kinases, Their Inhibitors and Their Regulation.

Johnson L.

La Jolla, CA: San Diego Supercomputer Center/Protein Kinase Resource (PKR)/Laboratory of Molecular Biophysics. 2002

Retinoids inhibit protein kinase C-dependent transduction of 1,2-diglyceride signals in human colonic tumor cells.

Kahl-Rainer P, Marian B.

Nutr Cancer. 1994; 21(2):157-68.

1,2-Diglycerides with long-chain fatty acid residues related to nutritional fat (LCDGs) specifically affect growth and urokinase secretion in human colonic tumor cells, but not in normal mucosa. This allows them to advance and enhance carcinogenesis in the colon and rectum. SW480 colon carcinoma cells are LCDG sensitive in the same way as primary colonic tumor cells and have therefore been used as a model system to study the mechanism of LCDG action and to search for inhibitors of tumor development in the colon. Using this model system, we have shown that the effects of LCDGs are transmitted by protein kinase C and abolished by downregulation of the enzyme. Retinol, retinoic acid, and beta-carotene in nanomolar concentrations inhibit LCDG-induced growth and urokinase secretion and block stimulation of protein kinase C. Although retinol and retinoic acid at higher concentrations also display stimulatory activity, beta-carotene does not. At 100 nM, a concentration that can easily be reached in the plasma of humans, beta-carotene reduces LCDG-induced urokinase secretion about 50%. Inasmuch as beta-carotene does not have side effects due to intrinsic activities and storage effects, beta-carotene and foods rich in carotenes could be useful in the prevention of colorectal cancer

IL-4 biology: impact on normal and leukemic CLL B cells.

Kay NE, Pittner BT.

Leuk Lymphoma. 2003 Jun; 44(6):897-903.

This review provides a perspective on the role of IL-4 in relation to both normal and leukemic CLL B cells. IL-4 is a well-characterized cytokine known to be produced by normal T cells and have impact on normal B cell differentiation and proliferation. This cytokine and its receptor are now known to exist on CLL B cells. An autocrine pathway for CLL B cells is strongly supported by signaling events, alteration of apoptotic proteins and changes in apoptosis resistance. Based on the increasing knowledge regarding the IL-4 pathway unique opportunities for therapy are now available in B-CLL

Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6.

Khalfoun B, Thibault F, Watier H, et al.

Adv Exp Med Biol. 1997; 400B:589-97.

The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. In this study, we have examined the effects of polyunsaturated fatty acids (PUFAs) on the production of IL-6 by human unstimulated EC or EC stimulated with TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6 were measured by Sandwich ELISA. We have shown that the production of IL-6 was potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL-6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even used at the highest concentration, was ineffective. This inhibitory effect is PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode of action, since IL-6 is known to be involved in hematopoiesis, in the regulation of the immune response and in the inflammatory reaction, these results suggest that n-3 PUFAs may play a role in suppressing inflammation. Further studies are needed to elucidate the mechanism involved and the choice between the two fatty acids for clinical and therapeutic purposes

Adenovirus-mediated transfer of a p53 gene in ovarian cancer.

Kigawa J, Terakawa N.

Adv Exp Med Biol. 2000; 465:207-14.

Given the lack of effective conventional therapy, those patients with recurrent or refractory ovarian cancer should be considered for currently approved investigational gene therapy protocols. Several studies have shown a potential modality of p53 gene transfer in cancer gene therapy. We also developed a new recombinant adenovirus carrying a wild-type p53 gene (AxCAp53). Although the efficacy of AxCAp53 to suppression of cell growth was not sufficient, AxCAp53 increased sensitivity to CDDP in ovarian cancer cells with deletion of the p53 gene. The combination of CDDP and AxCAp53 may be a potential strategy for the therapy of CDDP resistant ovarian cancer

Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes.

Kipper-Galperin M, Galilly R, Danenberg HD, et al.

Int J Dev Neurosci. 1999 Dec; 17(8):765-75.

Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating activity. DHEA effectively protects animals from several viral, bacterial and parasitic infections and it was suggested that its age-associated decline is related with immunosenescence. In the present study we examined the ability of DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated glial cells and to change the course of acute central nervous system (CNS) inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98 and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2) production was not affected. However, daily administration of 0.5 mg DHEA to mice or 5 mg to rats did not change the clinical outcome of experimental autoimmune encephalomyelitis (EAE)

Cytokine deregulation in cancer.

Kurzrock R.

Biomed Pharmacother. 2001 Nov; 55(9-10):543-7.

Endogenous cytokines are aberrantly produced in many cancers, and serve as autocrine growth factors or indicators in immune response to the tumors. Hence, cytokine deregulation is likely to participate in the development or evolution of the malignant process. Over the last few years, endogenous cytokine levels have been correlated with phenotypic manifestations of cancer and with prognosis. For instance, serum IL-6 levels are elevated in both relapsed and newly-diagnosed Hodgkin's and non-Hodgkin's lymphoma, and these levels correlate with established prognostic features. Furthermore, in diffuse large cell lymphoma, serum IL-6 level is an independent prognostic variable for both complete remission and failure-free survival. Serum IL-10 levels are also elevated in lymphoid malignancies and predict outcome. In some cases, it may be that the balance between endogenous cytokine agonists and antagonists is disrupted. For instance, in chronic myelogenous leukemia, high cellular (leukocyte) levels of IL-1 beta and low levels of IL-1 receptor antagonist (IL-1RA) are seen in advanced disease and correlate with reduced survival. The molecular mechanisms underlying cytokine deregulation are now being investigated, with preliminary data suggesting heterogeneous genetic driving forces, including oncogene aberrations and viral infection

[Multiple actions of EGCG, the main component of green tea].

L'Allemain G.

Bull Cancer. 1999 Sep; 86(9):721-4.

Green tea, the most popular beverage in Japan and China, contains epicatechin-derived compounds which have been characterized in some epidemiological studies as having protective effects against cancer. Epigallo catechin-O-gallate (EGCG), the most active epicatechin in green tea was previously found to block the in vitro growth of many cancer cell lines and in vivo to strongly reduce tumor growth in cancer-bearing animals. Today, green tea consumption by animals is shown to markedly reduce VEGF-induced angiogenesis, a neo-vascularization process occurring in several physio-pathological conditions. EGCG is also able to inhibit endothelial cell growth in vitro and angiogenesis process in vivo. Elsewhere, EGCG has been described as a potent inducer of apoptosis and an inhibitor of telomerase activity. Because EGCG is acting on different processes, it could trigger various molecular mechanisms of action. Its anti-oxidant properties could explain its antagonistic action in some inflammatory processes. In summary, although no direct molecular target has been so far elucidated for EGCG, the multi-potentialities of this molecule, along with its broad bioavailability, render it very attractive as a putative curative drug for various diseases such as dermatosis, gout, atherosclerosis and cancer

Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro.

Li H, Cao Y, Berndt MC, et al.

Oncogene. 1999 Nov 18; 18(48):6785-94.

The telomere DNA polymerase (telomerase) and the tumor suppressor protein p53 are frequently associated with human cancers, and activation of telomerase and inactivation of p53 involved in cancer cell immortalization. In this report, we demonstrate a direct interaction of telomerase with p53 in the nuclear lysates of human breast cancer cells, and with recombinant human p53, by affinity chromatography and immunoprecipitation. On activity criteria, the interaction is between the carboxyl-terminal region of p53 and a region close to the amino-terminus of human telomerase-associated protein 1 (hTEP1). Incubation of recombinant p53 with nuclear telomerase extracts results in inhibition of telomerase activity, with the C-terminal region of p53 being essential for inhibition. This effect is not mediated by binding to telomerase substrate DNA, but requires the region near the N-terminus of hTEP1, in that a synthetic peptide derived from this region of hTEP1 similarly inhibits telomerase activity. Together, these in vitro interactions between telomerase and p53 suggest that the activity of telomerase may be regulated by p53, down-regulation of which in turn would favor up-regulation of telomerase activity in cancer cell development

Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis.

Liu L, Trimarchi JR, Navarro P, et al.

J Biol Chem. 2003 Aug 22; 278(34):31998-2004.

The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an anti-tumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome end-to-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other

In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress.

Maes M, Christophe A, Bosmans E, et al.

Biol Psychiatry. 2000 May 15; 47(10):910-20.

BACKGROUND: Psychologic stress in humans induces the production of proinflammatory cytokines, such as interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6), and that of the negative immunoregulatory cytokine, IL-10. An imbalance of omega6 to omega3 polyunsaturated fatty acids (PUFAs) in the peripheral blood causes an overproduction of proinflammatory cytokines. The omega3 PUFAs reduce the production of proinflammatory cytokines. METHODS: This study examines whether an imbalance in omega6 to omega3 PUFAs in human blood predicts a greater production of proinflammatory cytokines in response to psychologic stress. Twenty-seven university students had serum sampled a few weeks before and after as well as 1 day before a difficult oral examination. We determined the omega6 and omega3 fractions in serum phospholipids as well as the ex vivo production of IFN-gamma, TNF-alpha, IL-6, IL-10, and IL-5 by diluted whole blood stimulated with polyclonal activators. RESULTS: Academic examination stress significantly increased the ex vivo, stimulated production of IFN-gamma, TNF-alpha and IL-10, and the IFN-gamma/IL-5 production ratio. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had significantly greater stress-induced TNF-alpha and IFN-gamma responses than subjects with higher serum omega3 PUFAs and a lower omega6/omega3 ratio, respectively. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had a significantly higher stress-induced increase in the IFN-gamma/IL-5 ratio than the remaining subjects. CONCLUSIONS: Psychologic stress induces a Th-1-like or proinflammatory response in some subjects. An imbalance in the omega6 to omega3 PUFA ratio appears to predispose humans toward an exaggerated Th-1-like response and an increased production of monocytic cytokines, such as TNF-alpha, in response to psychologic stress. The results suggest that increased omega3 PUFA levels may attenuate the proinflammatory response to psychologic stress

Chemokines and Stealth Viruses: A Blueprint for Therapy in Infected Human and Animals.

Martin JW.

2002

Cytotoxic T cell immunity against telomerase reverse transcriptase in humans.

Minev B, Hipp J, Firat H, et al.

Proc Natl Acad Sci U S A. 2000 Apr 25; 97(9):4796-801.

Telomerase is a ribonucleoprotein enzyme which has been linked to malignant transformation in human cells. Telomerase activity is increased in the vast majority of human tumors, making its gene product the first molecule common to all human tumors. The generation of endogenously processed telomerase peptides bound to Class I MHC molecules could therefore target cytotoxic T lymphocytes (CTL) to tumors of different origins. This could advance vaccine therapy against cancer provided that precursor CTL recognizing telomerase peptides in normal adults and cancer patients can be expanded through immunization. We demonstrate here that the majority of normal individuals and patients with prostate cancer immunized in vitro against two HLA-A2.1 restricted peptides from telomerase reverse transcriptase (hTRT) develop hTRT-specific CTL. This suggests the existence of precursor CTL for hTRT in the repertoire of normal individuals and in cancer patients. Most importantly, the CTL of cancer patients specifically lysed a variety of HLA-A2(+) cancer cell lines, demonstrating immunological recognition of endogenously processed hTRT peptides. Moreover, in vivo immunization of HLA-A2.1 transgenic mice generated a specific CTL response against both hTRT peptides. Based on the induction of CTL responses in vitro and in vivo, and the susceptibility to lysis of tumor cells of various origins by hTRT CTL, we suggest that hTRT could serve as a universal cancer vaccine for humans

Mosby's Medical Dictionary, Fifth Edition 1998.

MMD.

1998; 5th

Study Says Gene Therapy Halts Cancer.

Modica P.

1996;

The evolving role of telomerase inhibitors in the treatment of cancer.

Mokbel K.

Curr Med Res Opin. 2003; 19(6):470-2.

Telomerase is a ribonucleoprotein that maintains telomeres and is essential for cellular immortality and tumour growth. The differential expression of telomerase in cancer cells makes it an attractive therapeutic target. Anti-sense oligonucleotides directed against the RNA template of hTR and small molecules that can interact and stabilise the G-quadruplex represent promising therapeutic strategies. Human trials investigating the potential role of the catalytic subunit hTERT as a universal cancer vaccine have already commenced. Alternative lengthening of telomeres (ALT) and efficacy delay remain important limitations to anti-telomerase therapy

Pyrrolidine dithiocarbamate inhibits the production of interleukin-6, interleukin-8, and granulocyte-macrophage colony-stimulating factor by human endothelial cells in response to inflammatory mediators: modulation of NF-kappa B and AP-1 transcription factors activity.

Munoz C, Pascual-Salcedo D, Castellanos MC, et al.

Blood. 1996 Nov 1; 88(9):3482-90.

Endothelial cells (EC) play a key role in the inflammatory response, both by the production of proinflammatory cytokines and by their interaction with leukocytes. Molecular genetic analysis has demonstrated that functional NF-kappa B sites are involved in the transcription of interleukin-6 (IL-6), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in response to inflammatory mediators. Thus, we have explored the effect of two inhibitors of the NF-kappa B activation, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), on the production of these cytokines by EC. Both PDTC and NAC inhibited, in a dose-dependent manner, the synthesis of IL-6, IL-8, and GM-CSF induced by tumor necrosis factor (TNF)-alpha or bacterial lipopolysaccharides (LPS) in human umbilical vein endothelial cells (HUVEC). PDTC appeared to prevent IL-6, IL-8, and GM-CSF gene transcription, as it blocked the induction of specific mRNA by TNF-alpha or LPS. The TNF-alpha mediated transcriptional activation of a chloramphenicol acetyltransferase (CAT) plasmid containing three copies of the -72 kappa B binding site from the IL-6 promoter was abrogated by PDTC. According to transfection experiments, electrophoretic mobility shift assays (EMSA) demonstrated that the antioxidant prevented the induction of NF-kappa B DNA-binding activity by TNF-alpha. Under the same conditions, PDTC by itself or in combination with TNF-alpha, enhanced the DNA-binding activity of AP-1, as well as c-fos and c-jun mRNA levels. Altogether, these results indicate that the antioxidant PDTC specifically inhibits the transcription of IL-6, IL-8, and GM-CSF genes through the inhibition of the NF-kappa B activation, while increasing the expression of AP-1. Our data make evident the antiinflammatory and immunoregulatory potential of the pharmacological inhibition of the NF-kappa B activation. In addition, PDTC and related molecules may be a useful tool to explore the expression of genes involved in the inflammatory response

Vitamin A-related compounds, all-trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases.

Murakami C, Takemura M, Sugiyama Y, et al.

Biochim Biophys Acta. 2002 Feb 20; 1574(1):85-92.

Retinoic acids, vitamin A-related compounds, are known to be inhibitors of telomerase. We found that fucoxanthin from the sea alga Petalonia bingamiae is a potent inhibitor of mammalian replicative DNA polymerases (i.e., pol alpha, delta and epsilon). Since fucoxanthin is a carotenoid (provitamin A-related) compound, we characterized the biochemical modes of vitamin A-related compounds including vitamin A and provitamin A in this report. Subsequently, we found that fucoxanthin, all-trans retinal (RAL, vitamin A aldehyde) and all-trans retinoic acid (RA, vitamin A acid) inhibited the activities of replicative DNA polymerases with IC(50) values of 18-190, 14-17 and 8-30 microM, respectively. On the other hand, all-trans retinol (vitamin A) did not influence any of the DNA polymerase activities. RA inhibited not only the activities of pol alpha, delta and epsilon with IC(50) values of 30, 28 and 8 microM, respectively, but of pol beta with an IC(50) value of 27 microM. The tested vitamin A-related compounds did not influence the activities of DNA polymerases from a higher plant, cauliflower, prokaryotic DNA polymerases, or DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. RAL and RA should be called selective inhibitors of mammalian DNA polymerases including telomerase, and RAL was a specific inhibitor of mammalian replicative DNA polymerases. As expected from these results in vitro, some of them could prevent the growth of NUGC-3 human gastric cancer cells, and especially RAL was a potent antineoplastic agent with an LD(50) value of 19 microM. The cells were halted at G1 phase in the cell cycle by RAL

Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB.

Muraoka K, Shimizu K, Sun X, et al.

Transplant Proc. 2002 Jun; 34(4):1335-40.

Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins.

Naasani I, Seimiya H, Tsuruo T.

Biochem Biophys Res Commun. 1998 Aug 19; 249(2):391-6.

Animal in vivo studies and human epidemiological observations indicated potent anticancer effects for tea. Here we demonstrate that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, an enzyme essential for unlocking the proliferative capacity of cancer cells by maintaining the tips of their chromosomes. Telomerase inhibition was elaborated in a cell-free system (cell extract) as well as in living cells. In addition, the continued growth of two representative human cancer cell lines, U937 monoblastoid leukemia cells and HT29 colon adenocarcinoma cells, in the presence of nontoxic concentrations of EGCG showed life span limitations accompanied with telomere shortening, chromosomal abnormalities, and expression of the senescence-associated beta-galactosidase. It is suggested that telomerase inhibition could be one of the major mechanisms underlying the anticancer effects of tea

Beyond Aspirin.

Newmark T.

2000;

Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin's lymphoma.

Niitsu N, Okamato M, Nakamine H, et al.

Eur J Haematol. 2002 Feb; 68(2):91-100.

Therapeutic approaches for non-Hodgkin's lymphoma (NHL) are currently based on the International Prognostic Index (IPI). Research on biological prognostic factors has been actively pursued in recent years, with serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) being identified as prognostic factors for NHL. Here, we determined that serum VEGF and IL-6 levels are independent prognostic factors for aggressive lymphoma. Compared with normal controls, serum VEGF and IL-6 levels were significantly higher in patients with aggressive lymphoma or adult T-cell leukemia/lymphoma. Furthermore, overall and disease-free survival rates for patients with high levels of VEGF or IL-6 were significantly poorer than for patients with low levels. In addition, the prognosis for patients with high levels of both serum VEGF and IL-6 was significantly poorer than that for patients with high levels of either VEGF or IL-6 or with low levels of both VEGF and IL-6. Multivariate analyses of a variety of prognostic factors, including the five IPI factors, revealed that serum VEGF and IL-6 were both independent prognostic factors for overall survival of aggressive lymphoma. Therefore, a combination of VEGF and IL-6 represents a useful prognostic factor for aggressive lymphoma

New molecular targets for cancer therapy.

Oliff A, Gibbs JB, McCormick F.

Sci Am. 1996 Sep; 275(3):144-9.

ATRA(ouble) in the treatment of acute promyelocytic leukemia.

Ozpolat B, Lopez-Berestein G, Mehta K.

J Biol Regul Homeost Agents. 2001 Apr; 15(2):107-22.

Acute promyelocytic leukemia (APL) is a unique disease that responds to differentiation-inducing effects of all-trans-retinoic acid (ATRA). ATRA induces complete clinical remissions (CRs) in most patients and now constitutes a standard therapy in patients with APL. However, CRs induced by ATRA are usually brief, and resistance to the therapy rapidly develops, leading to relapses in almost every patient; thus limiting the use of ATRA as a single agent. On the basis of clinical and in vitro studies, the following mechanisms have been proposed to explain ATRA resistance: 1) induction of accelerated metabolism of ATRA, 2) increased expression of cellular retinoic acid-binding proteins (CRABPs), 3) constitutive degradation of PML-RAR alpha, 4) point mutations in the ligand-binding domain of RAR alpha of PML-RAR alpha, 5) P-glycoprotein expression, 6) transcriptional repression by histone deacetylase activity, 7) isoforms of PML-RAR alpha, 8) persistent telomerase activity, and 9) expression of type II transglutaminase. In this review, we discuss the evidence provided in support of each mechanism, the mechanism's possible impact on the outcome of APL, and the newer approaches that are being employed to overcome ATRA resistance

Cytokines Online.

Pathfinder Encyclopedia.

2002

[Interleukin-6 and bone metastasis of renal cancer: molecular bases and therapeutic implications].

Paule B.

Prog Urol. 2001 Apr; 11(2):368-75.

Interleukin-6 (IL-6) is a multifunctional cytokine which provides multiple signals on various tissues and cells. In addition, IL-6 is produced by some human renal carcinoma cell lines in vitro and is expressed in a majority of primary renal cell carcinoma (RCC). Serum IL-6 influence the response to immunotherapy. IL-6 appears as a target for rational drug design highly promising for development of new cancer therapies. IL-6 effects are mediated by Stat. Stat (Signal transducers and activators of transcription) signaling pathways represent novel molecular targets for therapeutic implications in metastatic renal cell carcinoma. Inhibitors of Stat signaling pathway will not only block tumor growth by inducing apoptosis, but may also increase the sensitivity of tumors to conventional treatment (immunotherapy). The processes involved in tumor associated angiogenesis should lead to compounds able to interfere with angiogenesis. Il-6 has been implicated in the osteoclastic bone resorption and hypercalcemia associated with metastatic RCC. Different agents were shown to be effective in treating lytic bone disease mediated by osteoclast activation: bisphosphonates and osteoprotegerin

Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation.

Pendino F, Flexor M, Delhommeau F, et al.

Proc Natl Acad Sci U S A. 2001 Jun 5; 98(12):6662-7.

Human telomerase, a cellular reverse transcriptase (hTERT), is a nuclear ribonucleoprotein enzyme complex that catalyzes the synthesis and extension of telomeric DNA. This enzyme is specifically activated in most malignant tumors but is usually inactive in normal somatic cells, suggesting that telomerase plays an important role in cellular immortalization and tumorigenesis. Terminal maturation of tumor cells has been associated with the repression of telomerase activity. Using maturation-sensitive and -resistant NB4 cell lines, we analyzed the pattern of telomerase expression during the therapeutic treatment of acute promyelocytic leukemia (APL) by retinoids. Two pathways leading to the down-regulation of hTERT and telomerase activity were identified. The first pathway results in a rapid down-regulation of telomerase that is associated with retinoic acid receptor (RAR)-dependent maturation of NB4 cells. Furthermore, during NB4 cell maturation, obtained independently of RAR by retinoic X receptor (RXR)-specific agonists (rexinoids), no change in telomerase activity was observed, suggesting that hTERT regulation requires a specific signaling and occurs autonomously. A second pathway of hTERT regulation, identified in the RAR-responsive, maturation-resistant NB4-R1 cell line, results in a down-regulation of telomerase that develops slowly during two weeks of all-trans retinoic acid (ATRA) treatment. This pathway leads to telomere shortening, growth arrest, and cell death, all events that are overcome by ectopic expression of hTERT. These findings demonstrate a clear and full dissociation between the process of tumor cell maturation and the regulation of hTERT mRNA expression and telomerase activity by retinoids. We propose telomerase expression as an efficient and selective target of retinoids in the therapy of tumors

Retinoic acid receptor alpha and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death.

Pendino F, Dudognon C, Delhommeau F, et al.

Oncogene. 2003 Dec 11; 22(57):9142-50.

Retinoids modulate growth and differentiation of cancer cells through activation of gene transcription via the nuclear retinoic-acid receptors (RAR) and retinoid-X receptors (RXR). Their use in differentiation therapy of acute promyelocytic leukemia (APL) represents a model concept for reprogramming cancer cells. However, they also regulate antiproliferative genes whose functions do not mechanistically concur to this program. Recently, we have shown that, independently of maturation, a long-term all-trans retinoic acid (ATRA) treatment of the maturation-resistant APL cell line (NB4-LR1) represses telomerase (hTERT), leading to telomere shortening and death. Using retinoid-receptor-specific agonists, we demonstrate herein that cross-talk between RARalpha and RXR dual-liganded to their respective agonists resulted in strong synergistic downregulation of hTERT and subsequent cell death. Importantly, unlike ATRA, this synergy was obtained at very low agonist concentrations and occurred in other ATRA maturation-resistant APL cells. These findings provide the first demonstration that dual-liganded RXR and RARalpha signaling should allow efficient targeting of telomerase in differentiation-resistant tumor cells. Such a combination therapy might hold promise in clinic to avoid side effects of ATRA whose administration can indiscriminately activate all RARs. Given the tissue-specific expression of RARs, a tissue-selective therapy targeting telomerase in tumor cells by synthetic agonists can be envisioned

Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel.

Penson RT, Kronish K, Duan Z, et al.

Int J Gynecol Cancer. 2000 Jan; 10(1):33-41.

In vitro work suggests that cytokines may be important modulators of the cytotoxic effects of paclitaxel and subsequent drug resistance. This has been investigated in vivo in patients with ovarian cancer by ELISA. There was consistently elevated expression of IL-6 and IL-8 but not MCP-1, IL-1beta, IL-2, GM-CSF or TNFalpha. Peritoneal fluid concentrations of IL-6, IL-8 and MCP-1 were two to three logs greater than serum concentrations. Elevated concentrations of IL-6 correlated with a poor final outcome (P = 0.039), and increased IL-6 and IL-8 correlated with a poor initial response to chemotherapy (P = 0.041 and P = 0.041, respectively). There was a relatively clear pattern of change in all three cytokines. In serum, IL-6, IL-8 and MCP-1 decreased with the administration of steroids prior to paclitaxel, and increased in the 24 h after paclitaxel. Postoperative drainage fluid was relatively acellular, preventing flow-cytometric analysis of epithelial cells for apoptosis, but suggested activation of T cells by paclitaxel. IL-6 and IL-8 appear to be of prognostic importance in epithelial ovarian cancer. Treatment with paclitaxel is associated with an increase in expression of a limited number of cytokines in patients with ovarian cancer, notably IL-6, IL-8 and MCP-1

Plasma cytokine levels and monocyte activation in patients with obstructive jaundice.

Puntis MC, Jiang WG.

J Gastroenterol Hepatol. 1996 Jan; 11(1):7-13.

Some monocytic cytokines are important immune regulators. We have investigated cytokine production by monocytes and the blood levels of IL-1 beta, IL-6, TNF alpha, and TGF beta, in patients with obstructive jaundice. The supernatant from LPS stimulated monocytes from jaundiced patients released significantly increased quantities of TNF alpha by both bioassay and radioimmunoassay (RIA) (12.4 +/- 2.5 fmol/mL and 32.6 +/- 8.3 fmol/mL, respectively, for jaundice, compared with 1.6 +/- 0.3 fmol/mL and 2.4 +/- 0.5 fmol/mL respectively for controls, and also of IL-6 (54.8 +/- 5.0 fmol/mL in jaundice compared with 35.6 +/- 5.0 fmol/mL for controls). The production of IL-1 beta and TGF beta by stimulated monocytes was unchanged. Jaundiced patients had significantly higher plasma TGF beta, but TNF alpha and IL-1 beta were below the limits of detection. The highest monocyte TNF alpha and IL-6 levels were seen in malignant disease patients, especially those with a poor immediate prognosis. We conclude that the production of some cytokines by monocytes is up-regulated in patients with obstructive jaundice

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Reddi K, Henderson B, Meghji S, et al.

Cytokine. 1995 Apr; 7(3):287-90.

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB.

Riehemann K, Behnke B, Schulze-Osthoff K.

FEBS Lett. 1999 Jan 8; 442(1):89-94.

Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation

Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways.

Saliou C, Rihn B, Cillard J, et al.

FEBS Lett. 1998 Nov 27; 440(1-2):8-12.

The bioflavonoid silymarin is found to potently suppress both nuclear factor kappa-B (NF-kappaB)-DNA binding activity and its dependent gene expression induced by okadaic acid in the hepatoma cell line HepG2. Surprisingly, tumor necrosis factor-alpha-induced NF-kappaB activation was not affected by silymarin, thus demonstrating a pathway-dependent inhibition by silymarin. Many genes encoding the proteins of the hepatic acute phase response are under the control of the transcription factor NF-kappaB, a key regulator in the inflammatory and immune reactions. Thus, the inhibitory effect of silymarin on NF-kappaB activation could be involved in its hepatoprotective property

Analysis of interleukin-6 gene expression in primary human gliomas, glioblastoma xenografts, and glioblastoma cell lines.

Sasaki A, Ishiuchi S, Kanda T, et al.

Brain Tumor Pathol. 2001; 18(1):13-21.

Our previous study showed that high-grade astrocytomas often expressed high interleukin (IL)-1beta production. Coexpression of IL-1beta and IL-6 has been found in a number of glioma samples and glioma cell lines. To characterize the expression of IL-6 in the human glioma microenvironment, we investigated surgically excised human gliomas, human glioblastoma xenografts, and human glioblastoma cell lines using the reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA). In the 29 primary gliomas, transcripts of IL-6 were less frequently detectable (55.6%) than those of IL-1beta (72.4%) or those of IL-10, IL-8, or IL-1alpha (>80% each). As for IL-6 gene expression, little or no transcription was observed in low-grade astrocytomas, oligodendroglial tumors, and 1 ependymoma. Strong IL-6 gene expression was found in only 5 of 9 glioblastomas. Immunohistochemically, IL-6 antigen was localized in the tumor cells and macrophages in 4 of 7 glioblastomas. In 3 glioblastomas transplanted into nude mice, both IL-1beta and IL-6 were detected only in 1, but othercytokines (IL-8, IL-10, and IL-1alpha) were detected in all 3 xenografts by RT-PCR. Two cell lines both showed IL-6 expression at the mRNA level, and in a cell line with a high level of IL-6 and IL-1beta transcripts, significant production of IL-6 was observed by IHC and ELISA. We concluded that IL-6 produced in tumor tissue may be involved in tumor progression in some glioblastomas, but not in low-grade astrocytomas and oligodendroglial tumors, and that IL-6 gene expression is closely correlated with IL-1beta expression in biopsy tissue, xenografts, and cultures of human gliomas

Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin.

Scambia G, De Vincenzo R, Ranelletti FO, et al.

Eur J Cancer. 1996 May; 32A(5):877-82.

The aim of this study was to test the antiproliferative activity of silybin, a flavonoid, on human ovarian and breast cancer cell lines. Since flavonoids are thought to act through Type II oestrogen binding sites (Type II EBS), silybin binding to Type II EBS was also examined. Silybin, used in concentrations from 0.1 to 20 microM, exerted a dose-dependent growth inhibitory effect on OVCA 433, A2780 parental and drug-resistant ovarian cancer cells, and MCF-7 doxorubicin (DOX)-resistant breast cancer cells (IC50 = 4.8-24 microM). Both L and D diastereoisomers of silybin were effective in inhibiting A2780 WT cell growth (IC50 = 14 and 20 microM, respectively). Flow cytometry revealed that silybin decreased the percentage of cells in the S and G2-M phases of the cell cycle with a concomitant increase in cells in the G0-G1 phase. Silybin was able to compete with [3H]E2 for nuclear but not cytosolic Type II EBS. Its affinity parallels its efficacy in inhibiting cell proliferation. Furthermore, silybin (0.1 and 1 microM) potentiates the effect of cisplatin (CDDP) (0.1-1 micrograms/ml) in inhibiting A2780 WT and CDDP-resistant cell growth. Similar results were obtained on MCF-7 DOX-resistant cells when silybin (0.1 microM) was associated with doxorubicin (0.1-10 micrograms/ml). As assessed by the Berembaum isobole method, the effect of silybin-CDDP and silybin-DOX combinations results in a synergistic action. Using the 'stem cell assay' described by Hamburger and Salmon [Science 1977, 197, 461-463], we found that silybin exerted a dose-dependent inhibition of clonogenic efficiency of cells derived from three ovarian tumours (IC50 = 7.4, 4 and 6.4 microM, respectively). Since CDDP and DOX are the two most commonly used drugs for gynaecological tumours, the clinical application of silybin is currently under investigation in our institute

Parthenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascular derangement and outcome in endotoxic shock in rodents.

Sheehan M, Wong HR, Hake PW, et al.

Mol Pharmacol. 2002 May; 61(5):953-63.

Parthenolide is a sesquiterpene lactone used in folk medicine for its anti-inflammatory activity. Recent in vitro studies have shown that this compound inhibits the nuclear factor (NF)-kappaB pathway. This study examines the effect of parthenolide in endotoxic shock in rodents. Endotoxic shock was induced by administration of Escherichia coli endotoxin in rats. Three groups of rats received parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before endotoxin; another group received parthenolide (1 mg/kg) 3 h after endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed positive staining for nitrotyrosine, poly(ADP-ribose) synthetase (PARS) and apoptosis, whereas Northern blot analysis showed increased mRNA expression of inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma nitrate/nitrite were also found. Elevated lung levels of myeloperoxidase activity were indicative of infiltration of neutrophils. These inflammatory events were preceded by cytosolic degradation of inhibitor kappaBalpha (IkappaBalpha) and activation of nuclear NF-kappaB in the lung. In vivo pretreatment and post-treatment with parthenolide improved the hemodynamic profile and reduced plasma nitrate/nitrite and lung neutrophil infiltration in a dose-dependent fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated. Treatment with parthenolide also abolished nitrotyrosine formation, PARS expression, and apoptosis and reduced iNOS mRNA content in thoracic aortas. DNA binding of NF-kappaB was inhibited by parthenolide in the lung, whereas degradation of IkappaBalpha was unchanged. In a separate set of experiments, pretreatment or post-treatment with parthenolide significantly improved survival in mice challenged with endotoxin. We conclude that parthenolide exerts beneficial effects during endotoxic shock through inhibition of NF-kappaB

Clinical significance of telomerase activity in multiple myeloma.

Shiratsuchi M, Muta K, Abe Y, et al.

Cancer. 2002 Apr 15; 94(8):2232-8.

BACKGROUND: The clinical course of patients with multiple myeloma varies, and therefore it is important to evaluate the disease state. We studied the telomerase activity of myeloma cells as a possible prognostic factor in such patients. METHODS: Twenty five samples from patients with multiple myeloma were studied. We purified myeloma cells in bone marrow samples according to the expression of surface antigens, CD38 and CD45. CD38+/

Interleukin 13: a growth factor in hodgkin lymphoma.

Skinnider BF, Kapp U, Mak TW.

Int Arch Allergy Immunol. 2001 Dec; 126(4):267-76.

Classical Hodgkin lymphoma (cHL) is a malignant disorder of lymph nodes with distinctive clinical and pathologic features. These features are thought to be primarily due to the abnormal production of multiple cytokines by the malignant cell population of HL, the Reed-Sternberg (RS) cells. We have previously demonstrated that interleukin (IL)-13 expression is a common feature of HL and have studied its role as an autocrine growth factor for RS cells. IL-13 and IL-13R(alpha)1, the IL-13-specific receptor chain, are frequently expressed by HL-derived cell lines and by RS cells from biopsy material of tissues involved by HL. Neutralization of IL-13 in cultures of the HL-derived cell lines HDLM-2 and L-1236 leads to a dose-dependent inhibition of proliferation, and is associated with increased apoptosis in L-1236 cells. Signal transducer and activator of transcription (STAT) 6 is an important mediator of IL-13 signaling. STAT6 is constitutively activated in HL cell lines due to autocrine secretion of IL-13. STAT6 is also phosphorylated (P-STAT6) in RS cells from many primary HL samples, supporting the hypothesis that IL-13 signaling occurs in these malignant cells in vivo. Coexpression of IL-13, IL-13R(alpha)1 and P-STAT6 is uncommon in non-Hodgkin lymphomas. Following a description of the clinical and pathologic features of HL, this review will discuss the function of IL-13 as an autocrine growth factor for RS cells in HL and its potential role in mediating other features of this disease

Interleukins-6 and -11 expression in primary breast cancer and subsequent development of bone metastases.

Sotiriou C, Lacroix M, Lespagnard L, et al.

Cancer Lett. 2001 Aug 10; 169(1):87-95.

Breast cancers frequently metastasize to bone where they often cause extensive tumor-induced osteoclast-mediated osteolysis. Interleukin-6 (IL-6) and IL-11 are two cytokines exhibiting osteolytic properties through their potent stimulation of osteoclast formation. We investigated the expression of IL-6 and IL-11 in 99 invasive primary breast tumors by immunohistochemistry and in situ hybridization, respectively. We examined their potential as predictive factors for further development of bone metastases. 52/90 (57%) of tumor samples showed IL-6 cytoplasmic immunostaining. There was no significant association between IL-6 status and any of the classical prognostic factors. 15/89 (17%) of the tumor samples expressed IL-11 mRNA. A positive IL-11 mRNA status was associated with a low tumor grade (P=0.05). Tumors expressing IL-11 mRNA had a statistically significant (P=0.002) higher rate of bone metastases occurrence (12/15, 80%) than IL-11 negative tumors (27/74, 37%). Such association was not found for IL-6. Our findings demonstrate for the first time IL-11 gene expression in some primary invasive breast tumors and suggest the potential of this cytokine as possible biological predictive factor for the development of bone metastases

Stem cell transplants found superior.

Stephenson J.

JAMA. 2000 Feb 16; 283(7):870.

Polyphenols as cancer chemopreventive agents.

Stoner GD, Mukhtar H.

J Cell Biochem Suppl. 1995; 22:169-80.

This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice turmeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells.

Suzuki YJ, Aggarwal BB, Packer L.

Biochem Biophys Res Commun. 1992 Dec 30; 189(3):1709-15.

Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-kappa B activation. The present study was based on reports that antioxidants which eliminate ROS should block the activation of NF-kappa B and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, alpha-lipoic acid, prior to the stimulation of cells was found to inhibit NF-kappa B activation induced by tumor necrosis factor-alpha (25 ng/ml) or by phorbol 12-myristate 13-acetate (50 ng/ml). The inhibitory action of alpha-lipoic acid was found to be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was required for N-acetylcysteine. These results indicate that alpha-lipoic acid may be effective in AIDS therapeutics

Genistein inhibits constitutive and inducible NFkappaB activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells.

Tabary O, Escotte S, Couetil JP, et al.

Am J Pathol. 1999 Aug; 155(2):473-81.

The inflammatory pathogenesis in airways of patients with cystic fibrosis (CF) is still unresolved. We demonstrate here that in in situ human DeltaF508 homozygous CF bronchial tissues, submucosal gland cells exhibit an absence of inhibitor factor kappaBalpha (IkappaBalpha) and high levels of chemokine interleukin-8 (IL-8) expression. These results were confirmed by cultured human CF bronchial gland cells in which a lack of cytosolic IkappaBalpha and high levels of constitutively activated nuclear factor kappaB (NFkappaB) associated with an up-regulation of IL-8 production (13-fold increase) were found when compared to non-CF (control) disease bronchial gland cells. We also demonstrated that the isoflavone genistein, a well known CFTR mutant Cl(-) channel stimulator, significantly reduces the endogenous and Pseudomonas aeruginosa lipopolysaccharide-induced IL-8 production in cultured CF bronchial gland cells by increasing cytosolic IkappaBalpha protein levels. Overall, results show that genistein is a potent inhibitor of the activated NFkappaB identified in CF gland cells. This strong inhibition of constitutively activated NFkappaB and the resulting down-regulation of IL-8 production by genistein in the CF gland cells highlights the key role played by cytosolic IkappaBalpha in the regulation of inflammatory processes in CF human airway cells

Non-steroidal anti-inflammatory drugs inhibit telomerase activity in head and neck squamous carcinoma cell lines.

Thurnher D, Bakroeva M, Formanek M, et al.

Head Neck. 2001 Dec; 23(12):1049-55.

BACKGROUND: Antiproliferative effects in neoplastic cells of different origin have been attributed to non-steroidal anti-inflammatory Drugs (NSAIDs) during the past few decades. METHODS: We tested the influence of NSAIDs and hydrocortisone on cell lines derived from head and neck squamous cell cancer (HNSCC) and on normal oral mucosal keratinocytes. Cell numbers were assayed by cell counting, proliferation, telomerase activity with a colorimetric assay, and cell cycle distribution by flow cytometry. RESULTS: In the neoplastic cell lines indomethacin and ibuprofen caused a dose-dependent reduction of cell numbers and telomerase activity without altering cell viability and increased the percentage of cells in G0/G1 phase. In normal oral mucosal keratinocytes, only minor effects could be detected in response to NSAIDs and hydrocortisone. CONCLUSION: These results demonstrate that NSAIDs have activity against HNSCC cells in vitro and may have clinical applications in combination with other therapeutic regimens

Circadian interleukin-6 secretion and quantity and depth of sleep.

Vgontzas AN, Papanicolaou DA, Bixler EO, et al.

J Clin Endocrinol Metab. 1999 Aug; 84(8):2603-7.

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep

Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications.

Vgontzas AN, Bixler EO, Lin HM, et al.

J Clin Endocrinol Metab. 2001 Aug; 86(8):3787-94.

Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 +/- 0.3 vs. 3.3 +/- 0.3 pM, P = 0.04; and 218.0 +/- 11.0 vs. 190.4 +/- 8.3 nM, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep

Advances allow expanded use of allogeneic stem cell transplantation.

Wright K.

M D Anderson Oncolog. 2000;2000 Jul-Aug 45

Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model.

Yang F, de Villiers WJ, McClain CJ, et al.

J Nutr. 1998 Dec; 128(12):2334-40.

Green tea polyphenols are potent antioxidants. They have both anti-cancer and anti-inflammatory effects. However, their mechanisms of actions remain unclear. In inflammation, tumor necrosis factor-alpha(TNFalpha) plays a pivotal role. NF-KB, an oxidative stress -sensitive nuclear transcription factor, controls the expression of many genes including the TNFalpha gene. We postulated that green tea polyphenols regulate TNFalpha gene expression by modulating NF-KB activation through their antioxidant properties. In the macrophage cell line, RAW264.7, (-)epigallocatechin gallate (EGCG), the major green tea polyphenol, decreased lipopolysaccharide (LPS)-induced TNFalpha production in a dose-dependent fashion (50% inhibition at 100 mmol/L). EGCG also inhibited LPS-induced TNFalpha mRNA expression and nuclear NF-KB-binding activity in RAW264.7 cells (30-40% inhibition at 100 mmol/L). Similarly, EGCG inhibited LPS-induced TNFalpha production in elicited mouse peritoneal macrophages. In male BALB/c mice, green tea polyphenols (given by oral gavage 2 h prior to an i.p. injection of 40 mg LPS/kg body wt) decreased LPS-induced TNFalpha production in serum in a dose-responsive fashion. At a dose of 0.5 g green tea polyphenols/kg body wt, serum TNFalpha was reduced by 80% of control. Moreover, 0.5 g green tea polyphenols/kg body wt completely inhibited LPS-induced lethality in male BALB/c mice. We conclude that the anti-inflammatory mechanism of green tea polyphenols is mediated at least in part through down-regulation of TNFalpha gene expression by blocking NF-KB activation. These findings suggest that green tea polyphenols may be effective therapy for a variety of inflammatory processes

[Expression of telomerase genes in human tumors].

Yuan X, Zhang B, Ying J, et al.

Zhonghua Bing Li Xue Za Zhi. 2000 Feb; 29(1):16-9.

OBJECTIVE: To investigate the correlation between the expression of telomerase genes and malignant phenotypes of human tumors and to compare the expression of telomerase genes and its activity reported in order to evaluate the role of detection of telomerase genes in tumor diagnosis. METHODS: With in situ hybridization, the expression and distribution of telomerase hTR and hTRT genes were observed in 78 cases of human cancer tissues, 20 cases of precancerous lesions and 28 of benign lesions. The results were statistically analyzed. RESULTS: hTR and hTRT were detected in 85% (66/78) and 82% (64/78) of the primary cancers. While in the adjacent tissues, the positive rates were only 3% (2/78) and 5% (4/78). In 20 precancerous cases, the positive rate for hTR and hTRT were 20% (4/20) and 15% (3/20) and the positive cases in 28 benign lesions were 0 and 1/28 (4%), respectively. The positive detection of hTR and hTRT expression in cancer group were significantly different from those in the adjacent tissues, precancerous cases and benign lesion group (P < 0.01). In analysing main types of the human cancers, the positive frequency of hTR and hTRT were 94% (15/16) and 88% (14/16) for the breast cancer, 85% (17/20) and 90% (18/20) for the colon cancer, 80% (8/10) and 80% (8/10) for the gallbladder cancer, 75% (6/8) and 75% (6/8) for the lung cancer, 75% (6/8) and 75% (6/8) for the stomach cancer, and 83% (5/6) and 83% (5/6) for the esophagus cancer, respectively. The expression level of telomerase hTR and hTRT correlated well with the malignancy and metastatic potentials in breast cancer, colon cancer and bladder cancer. Besides, the expressions of hTR and hTRT were noticed to be also highly correlated (P < 0.01). CONCLUSIONS: The expression of telomerase genes correlates with tumor malignant phenotypes, and may reflect the progression of tumors, and the detection of telomerase gene expression may be useful in a retrospective cancer research. It is worthwhile for further study to clarify whether screening of telomerase gene expression is able to become a new index for tumor diagnosis and prognosis

UCSD Team Demonstrates Potential for Widely Effective Cancer Vaccine 2000.

Zanetti M.

2000