Life Extension Magazine

Life Extension Magazine February 2008

Abstracts

CoQ10 and Cancer

Coenzyme Q10: its biosynthesis and biological significance in animal organisms and in humans.

Coenzyme Q10 (ubiquinone) is a naturally occurring compound widely distributed in animal organisms and in humans. The primary compounds involved in the biosynthesis of ubiquinone are 4-hydroxybenzoate and the polyprenyl chain. An essential role of coenzyme Q10 is as an electron carrier in the mitochondrial respiratory chain. Moreover, coenzyme Q10 is one of the most important lipophilic antioxidants, preventing the generation of free radicals as well as oxidative modifications of proteins, lipids, and DNA, it and can also regenerate the other powerful lipophilic antioxidant, alpha-tocopherol. Antioxidant action is a property of the reduced form of coenzyme Q10, ubiquinol (CoQ10H2), and the ubisemiquinone radical (CoQ10H*). Paradoxically, independently of the known antioxidant properties of coenzyme Q10, the ubisemiquinone radical anion (CoQ10-) possesses prooxidative properties. Decreased levels of coenzyme Q10 in humans are observed in many pathologies (e.g. cardiac disorders, neurodegenerative diseases, AIDS, cancer) associated with intensive generation of free radicals and their action on cells and tissues. In these cases, treatment involves pharmaceutical supplementation or increased consumption of coenzyme Q10 with meals as well as treatment with suitable chemical compounds (i.e. folic acid or B-group vitamins) which significantly increase ubiquinone biosynthesis in the organism. Estimation of coenzyme Q10 deficiency and efficiency of its supplementation requires a determination of ubiquinone levels in the organism. Therefore, highly selective and sensitive methods must be applied, such as HPLC with UV or coulometric detection.

Postepy Hig Med Dosw. 2005;59:150-9

Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective.

Antioxidants are emerging as prophylactic and therapeutic agents. These are the agents, which scavenge free radicals otherwise reactive oxygen species and prevent the damage caused by them. Free radicals have been associated with pathogenesis of various disorders like cancer, diabetes, cardiovascular diseases, autoimmune diseases, neurodegenerative disorders and are implicated in aging. Several antioxidants like SOD, CAT, epigallocatechin-3-O-gallate, lycopene, ellagic acid, coenzyme Q10, indole-3-carbinol, genistein, quercetin, vitamin C and vitamin E have been found to be pharmacologically active as prophylactic and therapeutic agents for above mentioned diseases. Antioxidants are part of diet but their bioavailability through dietary supplementation depends on several factors. This major drawback of dietary agents may be due to one or many of the several factors like poor solubility, inefficient permeability, instability due to storage of food, first pass effect and GI degradation. Conventional dosage forms may not result in efficient formulation owing to their poor biopharmaceutical properties. Principles of novel drug delivery systems need to be applied to significantly improve the performance of antioxidants. Novel drug delivery systems (NDDS) would also help in delivery of these antioxidants by oral route, as this route is of prime importance when antioxidants are intended for prophylactic purpose. Implication of NDDS for the delivery of antioxidants is largely governed by physicochemical characteristics, biopharmaceutical properties and pharmacokinetic parameters of the antioxidant to be formulated. Recently, chemical modifications, coupling agents, liposomes, microparticles, nanoparticles and gel-based systems have been explored for the delivery of these difficult to deliver molecules. Results from several studies conducted across the globe are positive and provided us with new anticipation for the improvement of human healthcare.

J Control Release. 2006 Jul 20;113(3):189-207

Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis.

Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.

Cardiovasc Toxicol. 2007;7(2):101-7

Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer.

An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q10 (CoQ10) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ10 in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg(-1) body wt) and the treatment was started by the oral administration of TAM (10 mg kg(-1) body wt day(-1)) and CoQ10 (40 mg kg(-1) body wt day(-1)) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase,

catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ10 restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.

Mol Cell Biochem. 2005 May;273(1-2):151-60

Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance.

Reactive oxygen species (ROS) are emerging as key effectors in signal transduction. This role of ROS is especially evident in the pathways leading to programmed cell death (PCD) elicited in response to certain stress stimuli and cytokines. In these pathways, cytotoxic ROS signaling appears to be mediated in part by activation of the c-Jun-N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) cascade. Another pathway that is under ROS-mediated control in some systems is that leading to activation of transcription factor nuclear factor-kappa B (NF-kappaB), which is a central regulator of immunity, inflammation and cell survival. Remarkably, new evidence has unveiled the existence of a reciprocal, negative control that NF-kappaB exerts on ROS and JNK activities. This NF-kappaB-imposed restraint on ROS and JNK signaling is crucial for antagonism of PCD elicited by the proinflammatory cytokine tumor necrosis factor (TNF)alpha and likely other triggers. Effectors of this antagonistic cross-talk between NF-kappaB and ROS/JNK pathways have recently been identified. Because of the key roles that the prosurvival function of NF-kappaB plays in organismal physiology and disease, gaining a further mechanistic understanding of this cross-talk and NF-kappaB-dependent survival may be key to developing new therapies for the treatment of widespread human illnesses, such as cancer and chronic inflammatory conditions.

Oncogene. 2006 Oct 30;25(51):6731-48

The NF-kappaB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease.

NF-kappaB/Rel transcription factors have recently emerged as crucial regulators of cell survival. Activation of NF-kappaB antagonizes programmed cell death (PCD) induced by tumor necrosis factor-receptors (TNF-Rs) and several other triggers. This prosurvival activity of NF-kappaB participates in a wide range of biological processes, including immunity, lymphopoiesis and development. It is also crucial for pathogenesis of various cancers, chronic inflammation and certain hereditary disorders. This participation of NF-kappaB in survival signaling often involves an antagonism of PCD triggered by TNF-R-family receptors, and is mediated through a suppression of the formation of reactive oxygen species (ROS) and a control of sustained activation of the Jun-N-terminal kinase (JNK) cascade. Effectors of this antagonistic activity of NF-kappaB on this ROS/JNK pathway have been recently identified. Indeed, further delineating the mechanisms by which NF-kappaB promotes cell survival might hold the key to developing new highly effective therapies for treatment of widespread human diseases.

Cell Death Differ. 2006 May;13(5):712-29

Energy-modulating vitamins—a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma.

Mitochondria are the major intracellular organelles producing ATP molecules via the electron transport chain. Cancer cells have a deviant energy metabolism, and a high rate of glycolysis is related to a high degree of dedifferentiation and proliferation. The overall net ATP production is diminished with cancer, which ultimately leads to cancer cachexia. The present study was designed to investigate the altered energy metabolism in cancer cells and to enhance ATP production in the normal host cell metabolism by enhancing the activities of mitochondrial enzymes, using energy-modulating vitamins, and thus prevent cancer cachexia. Female Sprague-Dawley rats were selected for the experimental study. Mammary carcinoma was induced by the oral administration of 7,12-dimethylbenz[a]anthracene (25 mg/kg body weight), and treatment was started by the oral administration of the energy-modulating vitamins riboflavin (45 mg/kg body weight per d), niacin (100 mg/kg body weight per d) and coenzyme Q10 (40 mg/kg body weight per d) for 28 d. Mitochondria were isolated from the mammary gland and liver of all four groups, and the Krebs cycle and oxidative phosphorylation enzymes were assayed. In mammary carcinoma-bearing animals, the activities of the Krebs cycle and oxidative phosphorylation enzymes were significantly decreased. These activities were restored to a greater extent in animals treated with energy-modulating vitamins. From these experimental results, one may hypothesize that the combination therapy of energy-modulating vitamins could be of major therapeutic value in breast cancer.

Br J Nutr. 2005 Jun;93(6):901-9

Suppression of azoxymethane-induced colonic premalignant lesion formation by coenzyme Q10 in rats.

Reactive oxygen species cause damage to proteins, lipids and DNA. Coenzyme Q10 (CoQ10) is a compound with mitochondrial bioenergetic functions. The reduced form of CoQ10 shows antioxidant activity. In the present study, effects of CoQ10 on development of azoxymethane (AOM)-induced aberrant crypt foci (ACF) and mucin-depleted foci (MDF) in F344 male rats were investigated. To induce ACF and MDF, 6-week old rats were given two weekly subcutaneous injections of AOM (15 mg/kg body weight) and also received a control diet or experimental diets containing CoQ10 (200 or 500 ppm) for 4 weeks, starting one day before the first dose of AOM. At 10 weeks of age, all animals were sacrificed and their colons were evaluated for numbers and sizes of ACF and MDF. Administration of 200 and 500 ppm CoQ10 resulted in reduction of ACF numbers, to 77% and 68% of the carcinogen control value, respectively. The percentages of ACF consisting of more than 4 crypts in these groups were also significantly lower than in the controls. Treatment with 500 ppm CoQ10 furthermore decreased the number of sialomucin-producing ACF and MDF per colon to 42% and 38% of the carcinogen control value without CoQ10, respectively. These results suggest that CoQ10 may be an effective chemopreventive agent against colon carcinogenesis.

Asian Pac J Cancer Prev. 2006 Oct-Dec;7(4):599-603

Serum cytokine levels of interleukin-1beta, -6, -8, tumour necrosis factor-alpha and vascular endothelial growth factor in breast cancer patients treated with tamoxifen and supplemented with coenzyme Q(10), riboflavin and niacin.

The prognostic significance of supplementing coenzyme Q(10) (CoQ(10)), riboflavin and niacin (CoRN) along with tamoxifen to breast cancer patients was evaluated by measuring the serum cytokine levels of interleukin (IL)-1beta, IL-6, IL-8, tumour necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor. In the present study, 84 breast cancer patients were randomized to receive a daily supplement of CoQ(10) 100 mg, riboflavin 10 mg and niacin 50 mg, one dosage per day along with tamoxifen 10 mg twice a day. Serum cytokine levels were elevated in untreated breast cancer patients (Group II) and significantly reduced after tamoxifen therapy for more than 1 year (Group III). When group III breast cancer patients were supplemented with CoRN for 45 days (Group IV) and 90 days (Group V) along with tamoxifen, a significant reduction in cytokine levels were observed (P < 0.05). Such a decrease in serum cytokine levels after CoRN supplementation in breast cancer patients may suggest good prognosis and efficacy of the treatment, and might even offer protection from metastases and recurrence of cancer.

Basic Clin Pharmacol Toxicol. 2007 Jun;100(6):387-91

Effect of coenzyme Q10, riboflavin and niacin on serum CEA and CA 15-3 levels in breast cancer patients undergoing tamoxifen therapy.

In breast cancer patients, it is not the primary tumour, but its metastases at distant sites that are the main cause of death. Circulating breast cancer tumour markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) are reliable indicators of impending relapse, in which an increasing tumour marker level is associated with a very likelihood of developing recurrence. In the present study, 84 breast cancer patients were randomized to receive a daily supplement of 100 mg coenzyme Q10 (CoQ10), 10 mg riboflavin and 50 mg niacin (CoRN) one dosage per day along with 10 mg tamoxifen (TAM) twice a day. Serum CEA and CA 15-3 levels were elevated in untreated breast cancer patients (group II) and their tumour marker levels significantly reduced upon tamoxifen therapy for more than 1 year (group III). Group III patients supplemented with CoRN for 45 d (group IV) and 90 d (group V) along with tamoxifen significantly reduced CEA and CA 15-3 levels. This study suggests supplementing CoRN to breast cancer patients along with tamoxifen reduces the serum tumour marker level and thereby reduce the risk of cancer recurrence and metastases.

Biol Pharm Bull. 2007 Feb;30(2):367-70

Cytokine therapy in advanced melanoma.

Patients with melanoma considered at high risk for recurrence or regional metastases often have to choose between adjuvant interferon therapy or enrolling in a clinical trial. High-dose interleukin-2 therapy has had limited success in producing durable responses in stage IV melanoma; this success has been offset by marked toxicity. High-dose interferon alpha therapy has consistently shown disease-free survival benefit in clinical trials but has marked toxicity. The overall survival benefit has been inconsistent and controversial. Treatment with granulocyte macrophage colony-stimulating factor has shown promise in early studies. Various cytokines have had some success in treating advanced stage melanoma but with marked toxicity. Cytokine therapy that is well-tolerated and consistently provides an overall survival benefit for high-risk melanoma patients has not been achieved. Cytokines will continue to have a role in therapy for advanced-stage melanoma, most likely in combination with other immunomodulatory therapy. The challenge is finding the right doses, frequency, combinations, and duration of treatment.

J Drugs Dermatol. 2007 Apr;6(4):374-8