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Chemoprevention with Dietary Supplements

Yushi Li, PharmD

Narinder Duggal, BSc(Pharm), CDE, MD, FRCPC

Breast Cancer

Vitamin D

Vitamin D is hypothesized to affect breast cancer through the activation of vitamin D receptor (VDR), a transcription factor found in breast cells. Polymorphisms of VDR have been associated with breast cancer risk, and activation of VDR by vitamin D has been shown to inhibit cell cycle and induce apoptosis. Epidemiological studies have demonstrated promising results for the use of high dose vitamin D in breast cancer prevention. In an observational study which matched 179 breast cancer patients to control volunteers without disease, women with breast cancer were found to have significantly lower levels of 25(OH)D. Additionally, women with 25(OH)D levels less than 20 ng/mL had an odds ratio of 3.54 for breast cancer than those with levels greater than 20 ng/mL. In a pooled analysis of two studies with 1750 participants, 25(OH)D level greater than 50 ng/mL was associated with a 50% decrease in breast cancer risk compared to level less than 12 ng/mL. In a meta-analysis of six studies, subgroup analysis showed th

at women taking greater than 400 IU/d of vitamin D had fewer cases of breast cancer compared to women taking less than 50 IU/d of vitamin D. Lastly, in a recent meta-analysis of 11 cohort and case-controlled studied, the pooled data from seven studies showed a 45% decrease in breast cancer risk for women with 60nmol/L of 25(OH)D compared to women with the lowest level of vitamin D.

Fish oil

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are main forms of polyunsaturated omega-3 fatty acids in fish oil that are involved in the body’s biological functions. One hypothesis of fish oil’s benefit in breast cancer prevention is its ability to modulate eicosanoid metabolism. Whereas omega-6 polyunsaturated fatty acids are converted by cyclo-oxygenase 2 enzymes into pro-inflammatory prostaglandin E2, EPA and DHA result in less inflammatory prostaglandins. In a case-controlled study which included 241 patients presenting with non-metastatic invasive breast carcinoma and 88 patients with benign breast diseases as controls, women in the highest tertile of DHA had an odds ratio of 0.31 (95% CI 0.13-0.75) compared to women in the lowest tertile. Women in the highest tertile of the long-chain n-3 to total n-6 ratio had an odds ratio of 0.33 (95% CI 0.17–0.66) compared to women in the lowest tertile.

Prostate Cancer

Vitamin D

Vitamin D supplementation to prevent prostate cancer has produced mixed results. A meta-analysis of 11 prospective and case-control studies comprising of 7806 subjects and 3124 prostate cancer cases failed to identify an association between serum 25(OH)D level and risk of prostate cancer. On the contrary, data from the Physicians’ Health Study found physicians with 25(OH)D less than 28 ng/mL had twice the incidence of aggressive prostate cancer (OR 2.1, 95% CI 1.2—3.4). Likewise, a nested case-control study of 90 Kaiser Foundation cases and 91 controls found a trend toward reduced risk for prostate cancer (RR 0.41) in men with serum 25(OH)D greater than 28 ng/mL. It has been hypothesized that vitamin D levels may be associated with disease progression rather than disease occurrence. For example, three polymorphisms in VDR are associated with higher Gleason Score (summary odds ratio of 1.12). Furthermore, vitamin D level might be more important in early stages of carcinogenesis, before prostate cells lose their 1-alpha-hydroxylase activity, which may reduce the cells’ ability to activate 25(OH)D to produce tumor suppression.

Colorectal Cancer

Fish oil                       

EPA and DHA have chemopreventive effects against colorectal cancer through multiple mechanisms, including alteration of cell membrane fluidity to modify signaling pathways, COX-2 inhibition to reduce inflammatory processes, and increased apoptosis of abnormal mucosal cells. Data from 24 European studies have found inverse correlation between colorectal cancer mortality and intake of fish. Likewise, Greenland Eskimos with over 10 g/d of EPA, DHA and docosapentaenoic acid had lower incidence of colorectal cancer compared to individuals on Western diet containing approximately only 1 to 2 g/d of fish oil. In randomized, placebo-controlled clinical trails, EPA 2 g/d and DHA 1.1 g/d for 3 to 6 months were effective at reducing crypt cell proliferation, increasing apoptosis, and decreasing the number and size of polyps in patients with or at high risk for colorectal cancer.

Vitamin D           

Multiple mechanisms of chemoprevention have been proposed, including down-regulation of the canonical Wnt signaling pathway that is active in colorectal cancer, increased expression of tumor suppressor protein DKK-1, and down-regulation of transcription of DKK-4, a target of the Wnt/beta-catenin pathway. Data on the benefits of vitamin D for colorectal cancer has been largely positive. In the National Health and Nutrition Examination Survey III (NHANES III), individuals with serum 25(OH)D greater than 80 nmol/L had approximately one fourth the risk of dying of colon cancer as those with vitamin D level less than 20 ng/mL (RR 0.28, 95% CI 0.11–0.68). This corresponds to a reduction of nearly 75% in mortality. In a pooled analysis of five studies, serum 25(OH)D level greater than 38 ng/mL was associated with an odds ratio of 0.45 (95% CI 0.28–0.69), corresponding to 55% lower risk of colorectal cancer compared to individuals with 25(OH)D of less than 16 ng/mL.

Probiotics           

Probiotics’ chemoprevention mechanisms include alteration of the metabolic activities of intestinal microflora, alteration of physicochemical conditions in the colon, binding of potential carcinogens, short chain fatty acid production, production of anti-tumorigenic or anti-mutagenic compounds, elevating the hosts’ immune response and altering the hosts’ physiology. In various epidemiological studies, diet containing Lactobacillus and Bifidobacterium was associated with reduced incidence of colon cancer. A 12-week, randomized, double-blind, placebo-controlled trial conducted in 37 colon cancer patients and 43 polypectomized patients, the combination of a prebiotic and Lactobacillus and Bifidobacterium significantly reduced DNA damage in the lining of the colon and decreased growth and reproduction of colon cells.

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