Leukemia

Hormones and metabolism

The development of acute leukemia is accompanied by abnormalities in levels of cholesterol and some lipids (Baroni S et al 1994; Baroni S et al 1996; Moschovi M et al 2004). In particular, AML and ALL patients have low levels of high-density-lipoprotein cholesterol (Baroni S et al 1994; Baroni S et al 1996; Moschovi M et al 2004). Upon treatment, cholesterol levels return to normal in patients that respond to treatment, suggesting that cholesterol could be used as a marker to monitor chemotherapy (Baroni S et al 1994; Baroni S et al 1996; Moschovi M et al 2004). Research using specific types of leukemia cells (HL-60 cells) and showing that cholesterol is required for cells to progress through cell division (Fernandez C et al 2004) may explain the link between low cholesterol levels and acute leukemia that is characterized by the failure of cells to reach maturity.

Levels of the anti-inflammatory hormone cortisol are elevated in AML, CML,(Everaus H et al 1997; Singh JN et al 1989) and CLL (Everaus H 1992) patients. These high levels of cortisol, a powerful immunosuppressive agent, are associated with impaired immune cell responses (Everaus H 1992; Everaus H et al 1997) and may be partially responsible for the immune dysfunction seen in these patients.

DHEA. The hormone dehydroepiandrosterone (DHEA) has been shown to favorably alter inflammatory cytokines such as interleukin-2 in leukemic mice (raghi-Niknam M et al 1997). DHEA favorably modulated the immune dysfunction that occurred during leukemia retrovirus infection in old mice (Inserra P et al 1998) and prevented leukemia growth (Catalina F et al 2003).

DHEA might be effective in supporting healthy immune function in leukemia patients with a DHEA deficiency, which can be determined by a blood test (Uozumi K et al 1996). DHEA is contraindicated in both men and women with certain hormone-related cancers.

Nutritional therapy

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): http://www.genzymeimpath.com/lymphoma_leukemia.html.

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.

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.

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.