Health Concerns

Leukemia

Integrative Interventions

Balanced and adequate nutrition is especially important for cancer patients, and nutritional support may benefit individuals with leukemia (Begum 2012; Lobato-Mendizábal 1989; Viana 1994; Taj 1993). Conversely, malnutrition has been associated with worse outcomes in leukemia (Begum 2012; Lobato-Mendizábal 1989; Viana 1994), increased risk of infection (Scrimshaw 2010; Taj 1993), and poor therapy tolerance with increased risk of relapse (Viana 1994).

Green Tea and Epigallocatechin Gallate (EGCG)

Several human clinical trials have suggested that green tea decreases leukemia risk. In two such studies involving adults with leukemia, green tea consumption was associated with a 50% decreased risk of leukemia. The association was dose-dependent in that risk was reduced as the number of cups of tea consumed per day and number of years of tea consumption increased (Zhang 2008; Kuo 2009; Yuan 2011).

In animal models, EGCG has been shown to inhibit tumor growth, and in leukemia cell line experiments, it induced apoptosis via modulation of reactive oxygen species production (Nakazato 2005). Furthermore, laboratory studies showed using EGCG prior to curcumin induced apoptosis of CLL cells (Angelo 2009; Ghosh 2009). A study of a multi-nutrient mixture that included green tea extract found it suppressed tumor growth and induced apoptosis in a leukemia cell line (Roomi 2011). In AML, the genetic variation BCR-ABL is common and strongly correlates with increased risk of relapse and poor overall survival. EGCG suppressed the proliferation of AML cells harboring the FLT3 mutation in a study with four different leukemia cell lines (Ly 2013).

An important case series report from the Mayo Clinic detailed the cases of three early-stage CLL patients. On their own initiative, they began taking polyphenol-rich (EGCG) green tea extracts or green tea while under medical observation. All three had objective, measurable improvement in leukemia signs or laboratory indices, an indication of cancer regression, while taking only green tea extract and no other treatment. In two of these cases, disease regression after beginning green tea qualified as a “partial response” to treatment according to standard medical criteria. The authors pointed out that in all three cases, there was objective evidence of disease progression before taking green tea or green tea extract, and the observed disease regression began shortly after beginning green tea consumption. CLL ordinarily follows a gradual progressive course (Shanafelt 2006).

  • The first case was a 58-year-old woman with the small lymphocytic lymphoma (SLL) subtype of CLL. Twenty-nine months after diagnosis, she began developing enlarged lymph nodes; at 33 months, she began taking 630 mg green tea polyphenols per day. Over the next 12 months of taking green tea extract and no other treatment, the lymph nodes under her arms decreased in size by 50%, while her other lymph nodes became almost completely normal based on CT scan evidence. She did not require conventional cancer therapy during that time.
  • The second case was a 50-year-old woman diagnosed with early stage CLL. After five years, she developed fatigue and night sweats, and her lymphocyte count nearly doubled, a sign of leukemia progression. Shortly thereafter, she began taking 1200 mg green tea polyphenols daily; one month later, her white blood cell count had fallen 15%, and her lymphocyte count fell nearly 16%. After several months on green tea extract, she dropped the dose to 300 mg per day. Her lymphocyte count continued to move towards the normal range, and she continued without conventional treatment and without disease progression for 6.5 years at the time of the report.
  • In the third case, a 60-year-old woman was diagnosed with stage 0 CLL. She was followed for nine years, by which time her lymphocyte count had increased by over 60%. She commenced drinking eight cups of green tea daily; one week later, her white blood cell count had fallen 25% and her lymphocyte count fell over 20%. Over the next 4.5 months, her lymphocyte count continued to fall.

Omega-3 Polyunsaturated Fatty Acids (PUFAs)

Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid (PUFA) found in fish and fish oil, inhibits inflammation and has been associated with better weight maintenance and response to therapy, fewer complications, and improved survival in cancer patients (Murphy 2011; Gogos 1998; Jho 2004; Elia 2006; Zaid 2012).

Docosahexaenoic acid (DHA), another marine PUFA, was able to kill AML cells without harming normal blood-forming (hematopoietic) stem cells in a cell culture experiment (Yamagami 2009). Other evidence from cell culture studies shows that DHA enhances the toxic effect of imatinib on BCR-ABL-expressing human leukemia cell lines and increases arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant human leukemia cells (de Lima 2007; Quesenberry 2009).

Omega-3 PUFAs, in combination with chemotherapeutic drugs and radiotherapy, have shown beneficial effects in several cancers, including leukemia(Calviello 2009; Yamagami 2009).

In a clinical trial on Rai stage 0-I CLL patients, omega-3 fatty acids, in daily doses escalating from 2.4 g to 7.2 g, suppressed activation of the inflammatory regulator NF-κB and increased sensitivity of subjects’ lymphocytes to the chemotherapeutic drug doxorubicin (Adriamycin) (Fahrmann 2013).

Vitamin D

Vitamin D helps promote healthy cellular differentiation, and several lines of epidemiologic and preclinical data highlight vitamin D’s potential as a preventive and therapeutic agent in a variety of cancers, including leukemia (Piemonti 2000; Trump 2010; Kennel 2013). Low levels of vitamin D have been observed in AML patients, with further reductions noted following chemotherapy (Naz 2013). Moreover, low blood levels of vitamin D3 have been associated with adverse outcomes in newly diagnosed and intensively treated adult AML patients (Lee 2014).

In AML, normal blood-producing (hematopoietic) cells are replaced by cancerous myeloblasts. These myeloblasts multiply uncontrollably, are unable to follow the normal process of differentiation, and then accumulate in the bone marrow. Vitamin D may help these AML myeloblasts differentiate properly (Gocek 2012). Indeed, several studies suggest that vitamin D3 can induce both differentiation and apoptosis in leukemic cell lines (Suzuki 2006; Kim, Mirandola 2012; Bunce 1997; Hughes 2010; Hall 2013).

In a clinical trial, 29 older adult patients with AML were treated with cytarabine, hydroxyurea (Hydrea, Droxia), and 1,25-dihydroxyvitamin D (active form of vitamin D) for 21 days. After the treatment period, cytarabine and hydroxyurea were discontinued, but the subjects continued taking active vitamin D. Thirteen subjects achieved complete remission, and 10 subjects achieved a partial response, equating to an overall 79% response rate. The overall median survival for patients who responded to therapy was 14 months (Slapak 1992). Active vitamin D treatment showed an important benefit for a potential side effect of cancer treatment in a clinical trial in 16 children with ALL. After the first year of treatment, lumbar spine bone mineral density was improved among subjects whose initial bone mineral density was low (Diaz 2008).

Vitamin C

High concentrations of vitamin C have been shown to induce apoptosis in several cancer cell lines, including leukemia cells, in cell culture experiments (Kawada 2013; Gonçalves 2013; Terashima 2013; Roomi 1998; Yedjou 2009; Harakeh 2007). Clinical research on vitamin C in various cancers has been conducted over the years, with some studies concluding that intravenous, and possibly oral, vitamin C therapy may confer clinically meaningful benefits for cancer patients (Park 2013; Ohno 2009). In a study published in 2014, intravenous vitamin C in combination with arsenic trioxide was administered to 11 subjects with AML. Study participants received one gram intravenous vitamin C daily along with arsenic trioxide five days weekly for five weeks. One subject achieved a complete response, one achieved a complete response without complete recovery of platelet count, and blasts disappeared from the peripheral blood and bone marrow of four subjects (Aldoss 2014).

There is evidence that vitamin C requirements may be increased in leukemia patients. In a study of 28 children hospitalized with ALL and 30 healthy controls, it was found that although patients’ vitamin C intake was more than twice that of control subjects, their vitamin C plasma and urinary concentrations were dramatically reduced compared to controls (Neyestani 2007).

Curcumin

Curcumin, the main active ingredient in the spice turmeric (Curcuma longa), has anti-inflammatory and anticancer properties (Aggarwal 2003). Curcumin has been shown to inhibit metastasis, invasion, and angiogenesis in animal models and to induce cell death in leukemia cell lines (Kim 2008; Duvoix 2005; Duvoix 2003; Pae 2007). In CLL cells, curcumin induced apoptosis and inhibited proteins essential for survival in one cell culture study (Ghosh 2009).

Curcumin induces apoptosis via multiple mechanisms, which may make it difficult for cancer cells to develop resistance to it. Furthermore, curcumin selectively kills cancer cells while sparing normal cells (Ravindran 2009). Curcumin has several anticancer mechanisms:

  • It induces apoptosis of leukemia cells (Pae 2007; Ghosh 2009; Mukherjee Nee Chakraborty 2007; Hayun 2009; Rao 2011)
  • It modulates pathways required for cell survival (Pae 2007; Ghosh 2009)
  • It inhibits cell division and proliferation (Anand 2008)
  • It inhibits metastasis (Anand 2008)
  • It inhibits a pathway by which cancer cells acquire new blood supply (angiogenesis)

Curcumin has also shown promising results when tested in combination with chemotherapeutic agents. In a six-week clinical trial on 50 CML patients, treatment with turmeric powder along with imatinib led to greater reductions in nitric oxide levels compared to imatinib alone. Non-beneficial forms of nitric oxide are elevated in some leukemias, and its reduction as a result of combined therapy of imatinib and turmeric powder may help in the treatment of CML (Ghalaut 2012). The apoptotic action of arsenic trioxide increased greatly when combined with curcumin in human AML cells. Similar synergistic effects of curcumin are observed with lonidamine, a mitochondria-targeted anticancer drug (Sánchez 2010). Curcumin in combination with rapamycin (Rapamune) significantly induced apoptosis in cells obtained from patients with CLL (Hayun 2009). In leukemia cell lines, curcumin showed synergistic effects in combination with bendamustine (Treanda) and idarubicin (Idamycin) (Alaikov 2007). Also, sequential administration of curcumin following EGCG extract from green tea in CLL cells showed greater apoptotic activity than either did alone (Ghosh 2009).

Melatonin

Melatonin, a hormone produced by the pineal gland, regulates the circadian rhythm (sleep-wake cycle) (Haimov 1997). Melatonin has also demonstrated anti-aging, immunomodulatory, antioxidant, and anticancer properties (Di Bella 2013; El-Sokkary 2003). Several epidemiologic studies suggest that high levels of melatonin may help prevent cancer, possibly by activating the tumor-suppressor molecule p53 (Santoro 2012). Melatonin has been shown to augment the efficiency of some leukemia therapeutic regimens in laboratory and human studies (Granzotto 2001; Lissoni 2000). In one clinical trial, melatonin combined with interleukin-2 prolonged survival time in patients with blood-related malignancies (Lissoni 2000). In a small case series, four CLL patients who had not received any previous treatment underwent treatment with a combination of melatonin, retinoids, cyclophosphamide, somatostatin, bromocriptine (Cycloset, Parlodel), and adrenocorticotropic hormone and had long-lasting partial remission with no reported toxicity. After 10 years, these patients did not experience disease recurrence. Moreover, the patients were able to undergo the treatment at home, while maintaining their usual lifestyle and activities (Todisco 2009).

Resveratrol

Resveratrol is a plant-derived polyphenol (Borriello 2014) found in grape skin, various fruits, Japanese knotweed, and red wine (Chen 2013; Ahmad 2014; Estrov 2003). It has been shown to inhibit growth and induce cell death in several mouse and human leukemia cell lines without harming normal white blood cells (Dörrie 2001; Gautam 2000; Joe 2002; Surh 1999; Quoc Trung 2013). In a laboratory model, resveratrol reduced the viability and capability of leukemia cells to divide (Lee 2008). In an AML cell line, resveratrol blocked production of inflammatory molecules, inhibited proliferation, caused cell cycle arrest, and induced apoptosis (Estrov 2003).

Resveratrol has the ability to sensitize many types of cancer cells, including AML and promyelocytic leukemia cells, to a range of chemotherapeutic agents including vincristine, doxorubicin, cisplatin (Platinol), gefitinib (Iressa), 5-Fluorouracil, bortezomib (Velcade), and gemcitabine (Gemzar). Experimental studies indicate that resveratrol can help overcome the chemoresistance of malignant cells by modulating apoptotic pathways and down-regulating drug transporters and proteins involved in tumor cell proliferation (Gupta 2011). Some patients with CML develop resistance to imatinib treatment, and resveratrol has induced cell death in imantinib-resistant leukemia cell lines (Can 2012). Also, resveratrol induced cell growth arrest and apoptotis in doxorubicin-resistant AML cells (Kweon 2010).

Combining resveratrol with perifosine or bortezomib potentiated each drug’s ability to induce cell death in a laboratory study (Reis-Sobreiro 2009). In CLL cells, resveratrol plus fludarabine and resveratrol plus cladribine (Leustatin) caused a higher rate of apoptosis in comparison with the single drugs alone (Podhorecka 2011). Arsenic trioxide, a potent anticancer drug used in patients with APL, is severely toxic to the heart muscle. In a rodent model, resveratrol was able to protect the cardiovascular system and decrease oxidative damage and pathological alterations created by arsenic trioxide (Zhang 2013). These studies suggest resveratrol may be useful in combination with other chemotherapeutic drugs, especially in older patients for whom there are limitations on the use of some aggressive treatments.

Genistein

Isoflavones present in soy have been shown in animal models to have cancer-preventing activity. Genistein, an isoflavone found in large quantities in soy beans, has inhibited growth in leukemia cell lines (Raynal 2008; Zhang, Sun 2012) and caused apoptosis and arrest of cell cycle development in adult T-cell leukemia cells (Yamasaki 2010; Yamasaki 2013). Moreover, genistein enhanced the cytotoxic effects of chemotherapeutic agents including arsenic trioxide and bleomycin in several leukemia cell lines (Sánchez 2008; Lee 2004). In cancer, changes to DNA often inhibit the genes responsible for the suppression of tumor formation. Treating leukemia cells with genistein reactivates these tumor suppressor genes. In one study, leukemic mice fed a genistein-enriched diet lived significantly longer than expected. The authors pointed out that because the half-life of genistein is longer in humans than mice, a soy-enriched diet could yield plasma isoflavone concentrations that have produced anti-leukemia effects in laboratory studies (Raynal 2008).

Apigenin

Apigenin, a natural plant flavonoid found at high levels in celery, parsley, thyme, and several other herbs has demonstrated cancer chemopreventive activity in several experimental models (Gonzalez-Mejia 2010; Balasubramanian 2007). It inhibits cell proliferation in several types of cancer cells and reduces the number and size of skin tumors that develop in response to chemical carcinogen or ultraviolet B radiation exposure (Balasubramanian 2007). Apigenin is toxic to leukemia cells and induces apoptosis in several leukemia cell lines (Ruela-de-Sousa 2010; Budhraja 2012; Monasterio 2004; Jayasooriya 2012; Kilani-Jaziri 2012).

Quercetin

Quercetin is a naturally occurring phytochemical found in many fruits and vegetables as well as black tea and red wine. Numerous preclinical studies have found that quercetin possesses anti-leukemic activity through a number of mechanisms (Lee, Chen 2011; Kawahara 2009; Philchenkov 2010). In addition, cell culture studies have found that quercetin is capable of sensitizing CLL cells to several chemotherapeutic agents (Russo 2010; Spagnuolo 2012; Spagnuolo 2011; Russo 2013). Quercetin may have synergistic effects with other phytochemicals as well, as shown by one study in which quercetin in combination with resveratrol dose-dependently induced cell death in CLL cells (Gokbulut 2013). Several studies have shown that quercetin and quercetin derivatives inhibit several tyrosine kinases, an important anticancer mechanism (Huang 2009; Lee 2002; Huang 1999). Alone or in combination with chemotherapeutic drugs, quercetin might benefit patients with CLL and other forms of cancer (Spagnuolo 2012).

Astragalus

Astragalus membranaceus, a Chinese medicinal plant, contains bioactive flavonoids and polysaccharides with potential anti-leukemic activity through several mechanisms (Jia 2013; Huang 2012; Liu 2010; Yan 2009; Yin 2013). It has also been shown to restore the function of impaired T cells in cancer patients and activate the host’s anticancer immunity (Cho 2007a; Cho 2007b). In a clinical trial involving 44 children with acute leukemia in complete remission, 20 subjects received 90 g astragalus daily along with conventional chemotherapy and 24 subjects received chemotherapy alone for one month. The combination treatment improved the function of dendritic cells, which are important in the process of immune response, compared to chemotherapy alone (Dong 2005).

Panax Ginseng

Panax ginseng has been used in China for thousands of years for its anticancer properties (Helms 2004; Kang 2011). Experimental studies have used extracts of Panax ginseng to induce cell death in human leukemia cells (Lee 2000; Nguyen 2010). In another study, an extract of ginseng enhanced the ability of vitamin D to induce normal, healthy differentiation of leukemic cells (Kim 2009). Total saponins of Panax ginseng, one of the main effective components of ginseng, is capable of inducing differentiation in leukemia cells (Zuo 2009). Recently, protective effects of Panax ginseng were reported in children recovering from cancer treatment. The authors suggested a ginseng extract might stabilize the immune system and observed that the extract prevented the usual increase in inflammatory molecules (cytokines) in children who underwent chemotherapy or stem cell transplantation for cancer (Lee 2012).

Reishi

Reishi (Ganoderma lucidum) is a medicinal mushroom highly esteemed in traditional Chinese medicine. The dried powder of Reishi was used as an anticancer therapy in ancient China. Preclinical studies support its application for cancer prevention and treatment (Sliva 2003; Yuen 2005). Reishi extracts have been shown to induce cell death in various white blood cell cancers such as lymphoma, leukemia, and multiple myeloma (Müller 2006). In each of these cancer types, Reishi extracts have been shown to prevent new tumors from arising, and in many cases have shrunk existing tumors or pre-cancerous masses (Lu 2001; Lu 2002; Oka 2010; Joseph 2011).

Reishi extract was shown to enhance immune response in patients with advanced cancers in one study (Gao 2003). In a cell culture study, reishi extract inhibited the growth of leukemia cells (Wang 1997). In a rodent model, the beta-glucan fraction of reishi induced anti-tumor immunity (Ooi 2000). Aggressive chemotherapy often leads to bone marrow suppression and loss of immune function in leukemia patients. In a rodent model, reishi stimulated bone marrow recovery and increased production of both red and white blood cells (Zhu 2007). Reishi also exhibits anticancer properties by modulating the activity of immune cells including B lymphocytes, T lymphocytes, dendritic cells, macrophages, and natural killer cells (Xu 2011), as well as by enhancing both the number and function of several types of immune system cells (Jan 2011; Wang, Zhu 2012; Jeurink 2008). Furthermore, reishi promotes specialization of dendritic cells and macrophages, which are essential in allowing the body to react to new threats, vaccines, and cancer cells (Cao 2002; Lai 2010; Jan 2011; Ji 2011; Chan 2005).

Reishi has the apparent ability to enhance immune cell function in healthy cells. Although leukemias are characterized by prolific expansion of malignant immune cell populations, and reishi has been shown to promote the expansion of healthy immune cell populations, several preclinical studies have shown that reishi kills leukemic cells or promotes their differentiation (Fukuzawa 2008; Gao 2012; Hsieh 2013; Wang, Zhou 2012; Lee, Hung 2011; Hsu 2011).

Indole-3-Carbinol and Diindolylmethane

Indole-3-carbinol (I3C), a naturally occurring component of cruciferous vegetables such as broccoli, kale, cabbage, and cauliflower, is a promising chemopreventive and anticancer agent. I3C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and myeloid leukemia cells (Aggarwal 2005). Preclinical evidence has shown that I3C inhibits the viability of ATLL cells in a dose-dependent manner, meaning as the concentration of I3C increases, ATLL cell viability decreases (Machijima 2009). After treatment with I3C, signs of damage including DNA fragmentation and a decrease in cell cycle proteins were observed in leukemia cells. In leukemic mice, I3C showed beneficial effects such as increased T cells, reduction in weight of the liver and spleen, and increased activity of immune cells (macrophages) compared to the non-treated leukemic mice (Lu 2012). Another study in leukemia cells found that I3C suppressed the inflammatory molecule NF-ĸB as well as NF-ĸBrelated genes, which might be the anticancer mechanism of I3C (Takada 2005). Importantly, I3C did not exert any inhibitory effects on normal white blood cells. In fact, I3C has demonstrated a protective effect against chemically-induced carcinogenesis in animals (Machijima 2009). In addition, several rodent model studies have reported that I3C has liver-protective effects against multiple carcinogens (Aggarwal 2005).

Diindolylmethane (DIM) is an I3C-related compound also found in cruciferous vegetables. Studies have shown that it too possesses anti-leukemic properties. A two-part study found that DIM inhibited T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation in cell culture and also reduced growth of T-ALL cells implanted into mice when they consumed DIM in their diet (Shorey 2012). Another study found that a synthetic DIM derivative induced apoptosis and inhibited growth in cultured AML. The researchers concluded that “…these findings suggest that diindolylmethanes are a new class of compounds that selectively induce apoptosis in AML cells” (Contractor 2005).

DIM also effectively protected rodents from radiation injury, which is a leukemia risk factor. It appears to mediate this effect by aiding in DNA repair but has other properties as well, including inhibition of radiation-induced apoptosis (Connell 2013; Fan 2013). It is a powerful free-radical scavenger, and its derivatives have shown promising anti-tumor potential in cell culture studies (Benabadji 2004).

Sulforaphane

Sulforaphane, a natural isothiocyanate found in cruciferous vegetables, demonstrated anti-leukemic properties in preclinicalstudies using ALL cell lines and T and B lymphocytes from childhood ALL patients, induced apoptosis, and inhibited cell cycle survival pathways in several ALL cell lines. Sulforaphane has also resulted in reduction of cancer burden in mice with ALL (Suppipat 2012) and shown the potential to exert anticancer actions in multiple ways (Zhang 2007; Nian 2009; Traka 2008; Thejass 2006; Choi 2008; Fimognari 2008):

  • detoxify cancer-causing compounds (carcinogens)
  • prevent the multiplication of cancer cells
  • promote cancer cell differentiation
  • enhance the activity of natural killer cells, a type of white blood cell charged with attacking tumors and virus-infected cells
  • combat metastasis (the spread of a tumor to different parts of the body)

In addition, sulforaphane has the ability to modulate the self-renewing properties of cancer stem cells (Kim, Farrar 2012). Sulforaphane resensitized leukemia stem cells when used in combination with imatinib (Lin 2012). Similarly, sulforaphane significantly enhanced the cytotoxic effect of arsenic trioxide and led to apoptosis in a panel of leukemic cell lines by inducing oxidative damage (Doudican 2010). Sulforaphane has been well tolerated in both animal and human trials (Zhang 2007; Lin 2012).

Garlic Extract

Epidemiologic studies, preclinical investigations, and clinical trials support the role of garlic extract as a potent anticancer agent (Yedjou 2012; Miron 2008). Ajoene, a natural sulfur-containing compound extracted from garlic, has anti-leukemia properties (Yedjou 2012; Dirsch 2002; Ahmed 2001; Hassan 2004). Apart from inhibiting proliferation and inducing apoptosis in several leukemia cell lines, ajoene was able to induce apoptosis in myeloblasts from CLL patients. Moreover, ajoene profoundly enhanced the cytotoxic effects of two chemotherapeutic drugs (cytarabine and fludarabine) in chemotherapy-resistant human myeloid leukemia cells (Hassan 2004; Ahmed 2001). Allicin, another compound derived from garlic, was shown to induce apoptosis in a leukemia cell line in one study (Miron 2008).

Olive Polyphenols

Epidemiologic evidence and animal studies suggest that olive oil may prevent the onset of cancer (Fabiani 2002; Escrich 2014; Fabiani 2006; Cardeno 2013). Virgin olive oil phenol extract prevented leukemia cells from multiplying by inducing apoptosis and differentiation in cell culture. It also prevented oxidative DNA damage, a hallmark of cancer, in leukemia cells (Casaburi 2013; Fabiani 2006; Fabiani 2008). Virgin olive oil contains the major antioxidant compound hydroxytyrosol, which exerted protective activity against cancer cells in a cell line study by arresting the cell cycle, thus stalling the multiplication of the cancer cells. No effect was observed after similar treatment of non-cancerous blood cells (Fabiani 2002).