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Nutritional Therapy

Apigenin. A flavone (ie, a class of flavonoids) that is present in fruits and vegetables (eg, onions, oranges, tea, celery, artichoke, and parsley), has been shown to possess anti-inflammatory, antioxidant, and anticancer properties. Many studies have confirmed the cancer chemopreventive effects of apigenin (Patel 2007).

Apigenin has shown to induce apoptosis in leukemia cells (Wang 1999; Budhraja 2012). In addition, apigenin inhibited the growth of human leukemia cells and induced these cells to differentiate (they became healthy mature cells) (Takahashi 1998; Kawaii 1999). Topoisomerases are enzymes involved in many aspects of leukemic cell DNA metabolism such as replication). In one study, apigenin was shown to inhibit topoisomerase-catalyzed DNA irregularities (Boege 1996).

Astragalus. Astragalus, an herb used for centuries in Asia, has exhibited immune-stimulatory effects. Astragalus potentiates lymphokine-activated killer cells (Chu 1988). One study found that astragalus could partially restore depressed immune function in tumor-bearing mice (Cho 2007a), while another concluded that “…astragalus could exhibit anti-tumor effects, which might be achieved through activating the…anti-tumor immune mechanism of the host” (Cho 2007b).

Astragalus has also shown to be beneficial against leukemia. It was observed in a clinical trial that astragalus induced apoptosis in a chronic myeloid leukemia cell line (Huang 2012).

Coffee.  Coffee, especially brews enriched with chlorogenic acid, protect cells against the DNA damage that leads to aging and cancer development (Bakuradze 2011; Hoelzl 2010; Misik 2010). Growing tumors develop the ability to invade local and regional tissue by increasing their production of “protein-melting” enzymes called matrix metalloproteinases. Chlorogenic acid—present in coffee—strongly inhibited matrix metalloproteinase activity (Jin 2005; Belkaid 2006). In addition, chlorogenic acid induced apoptosis in chronic myelogenous leukemia cells (Bandyopadhyay 2004).

Vitamins D3, E, K2, and B12. Vitamin D3 and its analogs may help certain leukemia cells (AML) to become, or differentiate into, normal cells (Srivastava MD et al 2004). However, a monthly complete blood count (CBC) to monitor serum calcium, and kidney and liver function, is necessary to prevent vitamin D3 toxicity.

Vitamin E levels are lower in CML patients compared to healthy individuals (Singh V et al 2000). Vitamin E (as the succinate salt), in combination with vitamin D3, promotes cell maturation in HL-60 leukemia cells (Sokoloski JA et al 1997).

Vitamin K2 analogs help normalize leukemia cells (Miyazawa K et al 2001). Vitamin K2 supplementation taken alone or with all-trans retinoic acid (ATRA) therapy may benefit myelogenous leukemia (Yaguchi M et al 1997).

Deficiency of vitamin B12 causes chromosome breaks and is a risk factor for ALL (Ames BN 1999; Skibola CF et al 2002). Vitamin B12 supplementation is thought to reduce chromosome damage that leads to ALL (Ames BN 1999).

Soy extract. Soy extracts contain high levels of genistein, an inhibitor of protein tyrosine kinase, an enzyme that becomes dysfunctional in cancer cells. Protein tyrosine kinase activity is reduced by genistein, subsequently impeding the growth of cancer cells (Carlo-Stella C et al 1996b; Carlo-Stella C et al 1996a).

Studies have shown that genistein increased the potency of the chemotherapeutic agent bleomycin against the leukemia cell line HL-60, and reduced the damage this agent normally causes to normal lymphocytes, thus it may reduce normal tissue toxicity associated with chemotherapy (Lee R et al 2004).

The benefits of soy extract may be more significant in leukemia cases with a mutant p53 gene, making the leukemia cells more sensitive to chemotherapy. For example, genistein derived from soy extracts has been shown to increases expression of the gene that helps to suppress cancer cell growth (i.e. normal p53 tumor suppressor gene) in solid tumors that acts to protect the body from cancer development (Lian F et al 1999).

The presence of mutant p53 genes is determined by a pathologist’s examination of the leukemia cells. Consult your physician to determine if the pathologist performing an immunohistochemistry test for mutant or functional p53 discovered mutant p53; alternatively ask your physician to perform this test via Genzyme Genetics (formerly IMPATH Laboratories):

Curcumin. An extract of the spice turmeric, curcumin acts in combination with the soy isoflavone genistein to reduce the number of leukemia-promoting properties, such as growth signals and pro-inflammatory cytokines that are over-produced in leukemia (Arbiser JL et al 1998).

Curcumin has been shown to:

  • Inhibit production of bFGF, a potent growth signal for cancer cells that is known to be over-produced in AML, CML, and ALL (Arbiser JL et al 1998).
  • Increase expression of the cancer-protective p53 gene in leukemia cell lines, thus making them more susceptible to cell death (Jee SH et al 1998).
  • Reduce the production of the inflammatory cytokine, TNF-alpha, that is over-produced in CML and ALL (Xu YX et al 1997).

Green and black tea. Epigallocatechin gallate (EGCG) in green tea blocks the production of vascular endothelial growth factor (VEGF), considered essential for leukemia growth and spread (Lee YK et al 2004). EGCG may be particularly useful in CLL, a leukemia type that relies heavily on VEGF for its survival. EGCG significantly increased the rate of cell death in 8 out of 10 CLL samples (Lee YK et al 2004). Green tea blocks the proliferation of lymphocytes from adult T cell leukemia patients (Li HC et al 2000). Theaflavins found in black tea have also been shown to be as potent as EGCG from green tea in blocking proliferation of leukemia cell lines (Lung HL et al 2004).

Essential fatty acids (EPA, DHA, and GLA). Several leukemias are associated with abnormally high levels of the inflammatory cytokines TNF alpha and IL-6 (Aguayo A et al 2000; Fayad L et al 2001). Docosahexaenoic acid (DHA) and gamma-linolenic acid (GLA) are essential fatty acids that suppress these dangerous inflammatory cytokines (De CR et al 2000; Purasiri P et al 1997). The use of GLA and DHA has been shown to improve the response of leukemia to chemotherapy (Liu QY et al 2000). GLA and eicosapentaenoic acid (EPA) have been shown to cause death in HL-60 leukemia cells (Gillis RC et al 2002). Furthermore, a recent Phase I/II clinical study in humans with solid cancer also showed that DHA may improve responses to paclitaxel and carboplatin chemotherapy (Harries M et al 2004).

Essential fatty acids DHA and EPA are derived from fish, primrose, and borage oils.

Antioxidants (lipoic acid and L-ascorbic acid). Lipoic acid is a powerful antioxidant with anti-aging effects (Hagen TM et al 1999; Lykkesfeldt J et al 1998). Exposure of the Jurkat leukemia cell line to lipoic acid increased cell death (apoptosis) of the cancer cells but did not affect lymphocytes from normal healthy individuals (Sen CK et al 1999). Lipoic acid activates the enzyme caspase that drives a particular type of apoptotic cell death (Sen CK et al 1999). Lipoic acid helps crippled, damaged immune cells (such as those of cancer patients) to function more normally (Sen CK et al 1997).

Research shows that lipoic acid, used in combination with vitamin D3, helps to support normal (versus cancerous) growth and maturation of leukemia cells (Sokoloski JA et al 1997).

Laboratory tests show L-ascorbic acid inhibits proliferation of HL-60 leukemia cells and supports their normal (versus cancerous) growth and maturation (Kang HK et al 2003). In fact, L-ascorbic acid is being assessed for the treatment of AML because laboratory tests showed that it blocked growth of three AML cell lines and fresh leukemic cells from three AML patients (Kennedy DD et al 2004; Park S et al 2004).

Whether or not use of antioxidants antagonizes or supports chemotherapy agents may depend on the type of leukemia, the drug used, and the dose of antioxidant. People undergoing chemotherapy should discuss the use of antioxidants with an oncologist and refer to the Cancer Chemotherapy chapter.

Nutritional supplementation for specific forms of leukemia

Promyelocytic Leukemia: The use of retinoic acid (derived from vitamin A) and its synthetic derivatives, often in combination with vitamin D3, is well established in promyelocytic leukemia. This strategy takes into account the underlying genetic problems in this type of leukemia (Huang ME et al 1988; Mann G et al 2001).

Chronic Myeloid Leukemia: Several dietary supplements share similarities with Gleevec®, (Manley PW et al 2002; Nakajima M et al 2003) the FDA approved drug for CML. These include curcumin, (Aggarwal BB et al 2003) genistein from soy extracts, (Carlo-Stella C et al 1996b) catechin from green tea, and alkylgylcerols from shark liver oil (Lee YK et al 2004; Pugliese PT et al 1998), all of which inhibit the activity of protein tyrosine kinase, an enzyme that is abnormal in CML cells. In addition, curcumin inhibits the production of growth factors and chemical messengers that are abnormal in CML, therefore reducing the leukemic cell’s ability to multiply and grow (Arbiser JL et al 1998; Xu YX et al 1997). Ajoene, a garlic extract, has been shown in some studies to have activity against CML cells (Hassan HT 2004).

Acute Myeloid Leukemia: Some studies have suggested that curcumin and genistein can block growth of AML cells by interfering with growth factors that are over-produced in AML cells (Arbiser JL et al 1998; Bhatia N et al 2001; Hurley MM et al 1996). L-Ascorbic acid is being clinically tested for AML after encouraging laboratory tests (Park S et al 2004). Studies have shown that resveratrol and ajoene are capable of killing AML cells (Asou H et al 2002; Estrov Z et al 2003; Hassan HT 2004; Xu B et al 2004). Moreover, ajoene has been shown to kill chemotherapy resistant AML cells that present particular difficulties in the older patients (Ahmed N et al 2001).

Acute Lymphocytic Leukemia: Curcumin and genistein have been shown to posses the ability to block inflammatory substances, such as TNF-alpha, that are observed in high levels in ALL (Arbiser JL et al 1998; Bhatia N et al 2001; Hurley MM et al 1996; Xu YX et al 1997).

Chronic Lymphocytic Leukemia: Epigallocatechin from green tea, curcumin from turmeric, and genistein from soy extracts have all been shown to block the production of growth factors such as VEGF (Arbiser JL et al 1998; Carlo-Stella C et al 1996b; Lee YK et al 2004) typically seen in high levels in CLL (Ferrajoli A et al 2001). Essential fatty acids have been shown to suppress other inflammatory factors, such as IL-6 and TNF-alpha that are seen in high levels in CLL (De CR et al 2000; Purasiri P et al 1997).

Panax Ginseng. Panax ginseng, also known as Korean ginseng, has been used in China for thousands of years as a popular remedy for varous diseases including cancer (Kang 2011). Researchers observed that panax ginseng extract suppressed growth in human promyelocytic leukemia cells by inducing apoptosis (Lee 2000; Nguyen 2010). Also, the ability of vitamin D to induce differentiation (ie, the process by which cancer cells transform into cells that appear to be normal to a greater degree, and therefore less aggressive) of leukemic cells was enhanced by panax ginseng (Kim 2009).

PSK. PSK, which is a specially prepared polysaccharide extract from the mushroom Coriolus versicolor, has been studied extensively in Japan where it is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda 2003; Noguchi 1995; Yokoe 1997). PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang 2000). PSK has been shown to enhance NK cell activity in multiple studies (Ohwada 2006; Fisher 2002; Garcia-Lora 2001; Pedrinaci 1999).

The coriolus mushroom has demonstrated anti-leukemic effects. In one study, coriolus suppressed the proliferation of leukemic cells by greater than 90% (Lau 2004). Other studies have confirmed these findings with the mechanism of action mediated via apoptosis (Ho 2006; Hirahara 2012

Reishi. The active constituents of Reishi mushroom include polysaccharides, a unique protein named LZ-8, and triterpenes (Bao 2001; Xu 2011; Yeh 2010). Among its broad-spectrum immune-boosting effects are the following:

  • 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’s effects on dendritic cells have been proven to boost the response to tetanus vac­cine; the mushroom’s proteins are also under investigation as “adjuvants” to emerging cancer DNA vaccines and other immune-based cancer treatments (Lai 2010; Chu 2011; Lin 2011; Zhu 2012).
  • Reishi polysaccharide triggers growth and development of bone marrow, where most immune cells are born; following bone marrow eradication by chemotherapy, Reishi increased production of both red and white blood cells (Zhu 2007). Reishi polysaccharides provide immune-boosting function to circulating cancer-killing white blood cells of various types (Xu 2011).
  • Reishi increases numbers and functions of virtu­ally all cell lines in the immune system, such as natural killer cells, antibody-producing B cells, and the T cells responsible for rapid response to a new or “remembered” antigen (Jan 2011; Wang 2012; Jeurink 2008).

Laboratory and animal studies confirm that Reishi stimulates an appropriate anticancer immune response while quashing a cancer-promoting inflam­matory one. A few small human studies have dem­onstrated Reishi ability to enhance immune function in patients with advanced cancers (Wang 1997; Ooi 2000; Gao 2003).

Reishi extracts have also proven useful in inducing cell death in various “white blood cell cancers” such as lymphoma, leukemia, and multiple myeloma (Muller 2006). In each of these cancer types, Reishi mushroom extracts have been shown to prevent new tumors from arising, and in many cases to shrink existing tumors or pre-cancerous masses (Lu 2001, 2002; Oka 2010; Joseph 2011). These effects, because they may stop a tumor in its tracks before it ever reaches a detectable or dangerous size, can be considered successful cancer prevention by immuno­surveillance (Lu 2001, 2002).

Shark liver oil. Alkylglycerols are naturally occurring ester-lipids that were first isolated from shark liver oil and used in the treatment of children with leukemia (BROHULT A 1958). Treatment of cancer cells with alkylglycerols lowered the cancer cell’s ability to reproduce and invade healthy cells (Wang H et al 1999). Animal studies show that alkylglycerols curtail tumor growth by blocking cancer cell blood vessel growth (Pedrono F et al 2004). Alkylgylcerols also inhibit protein kinase C, a protein critical in cell proliferation that is often deregulated in malignancy (Pugliese PT et al 1998). Shark liver oil is the main source of alkylglycerols and could be taken up to 100 mg, three times per day, for three months without side effects (Pugliese PT et al 1998). Shark liver oil should not be consumed without first consulting with your physician.

Sulforaphane. Sulforaphane, which is an isothiocyanate, is most highly concentrated in broccoli as well as in other cruciferous vegetables (eg, brussels sprouts, cabbage and cauliflower).

Sulforaphane detoxifies potential carcinogens, promotes apoptosis, blocks the cell cycle that is required for cancer cell replication, prevents tumor invasion into healthy tissue, enhances natural killer cell activity, and combats metastasis (Zhang 2007; Nian 2009; Traka 2008; Thejass 2006). Research has also demonstrated that sulforaphane is among the plant chemicals most potently capable of blocking the cancer-producing effects of ultraviolet radiation (Dinkova-Kostova 2008).

In a clinical trial, sulforaphane enhanced the efficacy of imatinib (a drug used in the treatment of chronic myelogenous leukemia) against leukemia cells (Lin 2012). It has also triggered apoptosis in leukemia cells (Moon 2009).

Garlic extract (Ajoene). Ajoene, a natural sulfur-containing compound extracted from garlic, has anti-leukemia properties (Ahmed N et al 2001; Hassan HT 2004; Xu B et al 2004). Ajoene has anti-thrombotic and cholesterol-lowering properties but has not been tested clinically. Laboratory tests show ajoene blocks division and growth of leukemia cell lines, lowers cholesterol biosynthesis through HMG-CoA-reductase inhibition, and causes death of CML cells (Hassan HT 2004).

Ajoene enhances the ability of two chemotherapeutic agents (cytarabine and fludarabine) to kill human AML cells that were previously resistant to chemotherapy (Ahmed N et al 2001; Hassan HT 2004). Ajoene is a promising new therapy for relapsed AML and AML in the elderly, which are more resistant to chemotherapy. Pure garlic supplements contain ajoene.

Vitamin A. Oral administration of vitamin A analogs as well as synthetic vitamin A derivatives helps to support normal growth and maturation of cells and is associated with remission rates as high as 90 percent when used to treat certain types of leukemia (Huang ME et al 1988; Mann G et al 2001; Okuno M et al 2004). Fat-soluble vitamin A (Retinyl palmitate) has been used to maintain long-term survival of children with AML (Skrede B et al 1994). Vesanoid (Tretinoin®), a vitamin A analog that inhibits cell division and allows myeloid cells to reach maturity and attain normal function, is approved for treatment of certain leukemias (Kerr PE et al 2001).

Studies have shown that chemotherapy drug resistance may be overcome using vitamin A derivatives in combination with vitamin D3 and its analogs (Defacque H et al 1996; Elstner E et al 1996; Miyauchi J et al 1997; Nakajima H et al 1996).

Vitamin A is available as the prescription drug Retinol (which is a vitamin A alcohol). Oral administration of water-soluble vitamin A may inhibit deficiency in those with malabsorption, a low protein intake, active infection, or undergoing antibiotic therapy. A monthly blood test to measure serum concentration of vitamin A is necessary to monitor for vitamin A-induced liver toxicity. Animal studies show that vitamin E protects against vitamin A toxicity and increases assimilation and storage of vitamin A (Jenkins MY et al 1999; St CM et al 2004).

Supplementation with vitamin A in patients being treated with synthetic retinoids or vitamin A analogs (mimics) for cancer should be avoided because of the potential toxicity with the combination. Supplementing with vitamin A to support healthy cell growth and maturation may be considered ONLY after consultation with your physician if you are also being treated for leukemia with synthetic vitamin A derivatives.

Resveratrol. Resveratrol, a plant polyphenol found in grapes and red wine, has been shown in scientific studies to inhibit the growth of leukemia cell lines. Resveratrol reduces the growth of AML cell lines and causes death in HL-60 leukemia cells (Su JL et al 2005). Resveratrol has been shown to block the proliferation of fresh AML cells taken from the bone marrow of five newly diagnosed patients (Asou H et al 2002; Estrov Z et al 2003). Exposure of the leukemia cell line U937 to concentrations of resveratrol similar to those found in red wine blocked cell proliferation but, in this case, did not increase cell death of these abnormal cells (Castello L et al 2005).

Studies of resveratrol in humans suggest it is safe, (Aggarwal BB et al 2004) but appropriate human doses for leukemia therapy have not been determined. However, a study in mice showed resveratrol, taken orally, only showed potential anti-leukemic activity at high doses of 80 mg/kg body weight (Gao X et al 2002). Supplementation with resveratrol to support healthy cell growth and maturation should be done ONLY after consulting with your physician if you are also being treated for leukemia.

Folic Acid. Studies have suggested that folate supplementation of a mother’s diet during pregnancy protects the child from childhood ALL (Thompson JR et al 2001) and that abnormalities in the genes responsible for folate metabolism are a known risk factor for adult and childhood ALL (Skibola CF et al 2002). However, folic acid supplementation during leukemia treatment should be approached with caution because it may interfere with the chemotherapy drugs being used to treat the leukemia.

The best example of this is the drug methotrexate. Methotrexate, a chemotherapy drug used to treat many different types of cancers including certain types of leukemias, works by competing with folic acid for a key enzyme used in cell growth. Since cancer cells grow much faster than normal cells, methotrexate works by interfering with the cancer cells’ ability to grow quickly. For example, methotrexate is used to treat childhood ALL (Cohen IJ 2004; Kisliuk RL 2003). However, supplementing with folic acid may interfere with methotrexate’s ability to limit cancer cell growth.

If a patient with leukemia or other cancer is being treated with methotrexate, or another anti-folic acid drug that is actually a folate analog, then folic acid supplementation should be avoided because it may interfere with methotrexate’s anti-cancer effect.

Melatonin. Melatonin, a hormone produced by the pineal gland during nighttime hours, regulates sleep and waking cycles in humans (Haimov I et al 1997). Additionally, it helps support the immune system by stimulating lymphocyte activity (El-Sokkary GH et al 2003).

The use of melatonin supplements in leukemia treatment was initially approached with caution (Conti A et al 1992). However, recent studies show that melatonin may augment the efficiency of leukemia treatment (Granzotto M et al 2001; Lissoni P et al 2000). A study in animals showed that melatonin sensitized a chemotherapy resistant leukemia cell line (P388) to treatment (Granzotto M et al 2001). Furthermore, a clinical study showed that melatonin supplementation supported the treatment of leukemia with the cytokine interleukin-2 (Lissoni P et al 2000). Melatonin supplementation and co-treatment with autologous or allogeneic cells has been proposed as a model for control of malignant beta-cell leukemia (Nir I et al 1999). The use of melatonin to support a healthy neuroendocrine system should be used with caution and ONLY after consultation with your physician if you are being treated for leukemia.