Supplements and Cancer

Questions from the Clinic:

Should I add this supplement to my program now? If so, how do I tell if it is working?

Curcumin

Curcumin is the principal polyphenol found in the rhizomes of turmeric – a flowering plant from the ginger family (1). Commonly incorporated into curries, tea, and cosmetics, curcumin functions as a natural, non-toxic colorant and preservative (2). Although its medicinal properties have been recognized since antiquity, scientists have only recently begun to unravel the compound’s mechanisms of action inside the human body. Many of curcumin’s therapeutic benefits, documented in a litany of chronic diseases, mostly stem from its potent antioxidant and anti-inflammatory effects (3). These properties may explain the considerable attention curcumin has received from researchers in the context of cancer. In a bibliographic search of studies conducted between 1924 and 2018, investigators noted that 37% of all papers written on curcumin specifically studied the compound’s effect on various cancers (1).

Figure 1: Image courtesy of Examine.com.

Today, interest in curcumin as an adjunctive therapy in oncology settings remains high, especially as the need for more effective cancer drugs grows. Unlike other chemotherapy agents, which often lead to an array of treatment-related adverse events, curcumin has few side effects beyond nausea, diarrhea, headache, and yellow stool (1,4). In clinical trials, researchers have demonstrated the safety of curcumin at doses ranging between 4,000 mg/day and 8,000 mg/day, and the compound is “generally recognized as safe” by the U.S. Food and Drug Administration (5,6). That said, curcumin has poor bioavailability within the human body, and its rapid metabolism and systemic elimination limits its utility as a natural treatment. To overcome these limitations, curcumin may need to be administered with piperine – the major active component of black pepper – in order to create a complex that can counteract cancer (2). Curcumin supplements are relatively inexpensive and can be purchased over the counter; the price per 1 g, a popular dose used in clinical trials like those in Table 1, ranges from $0.56 to as high as $16.66 (7).

Results from preclinical trials conducted in animals look promising, but human clinical trial maturation is necessary to further clarify the role of this bioactive dietary additive to impact cancer outcomes.

Table 1: Sampling of recent clinical trials investigating the clinical utility and safety of curcumin in patients with cancer.

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Green Tea Extract

Figure 2: Image courtesy of IndiaMart.com.

Green tea extract comes from the leaves of Camellia sinensis – a hardy evergreen shrub native to East Asia and the Indian subcontinent (8). To produce green tea, farmers immediately steam harvested leaves to prevent fermentation and degradation of the pigments giving the plant its green color (9). Unlike oolong and black teas, which contain varying degrees of tannins and theaflavins, green tea primarily consists of catechins (10,11). Between 50% and 80% of the catechin content in green tea is in the form of epigallocatechin-3-gallate (EGCG) and accounts for much of green tea’s health benefits (12). Results collected across multiple studies suggest that EGCG exerts anti-inflammatory effects, induces apoptosis, attenuates oxidative stress, inhibits angiogenesis, and blocks activation of receptor tyrosine kinases, which mediate signaling pathways tied with cancer (13).

That said, the strongest evidence for green tea extract’s ability to counteract cancer comes from studies performed in animal models. Because of differences in metabolism, data collected from these particular investigations cannot be readily extrapolated to humans (14). In an updated Cochrane review article published in 2020, authors noted that the quality of evidence supporting the use of green tea extracts in human patients with cancer is mixed. Results from experimental studies suggest supplementation decreases the risk for prostate cancer, but in other studies may increase the risk for gynecological cancers. For other conditions, like non-melanoma skin cancer, researchers observed no difference in cancer cases among patients treated with green tea extract (15). Like with curcumin, an underlying issue with treatment may be tied to bioavailability; tea consumption only leads to plasma catechin levels in the low-micromolar range (16). To overcome this issue, scientists are assessing the efficacy of green tea extracts when delivered through pills and capsules (17). At low doses, green tea extracts are well-tolerated but can result in treatment-related adverse events at high concentrations, namely hepatotoxicity (18). Future clinical trials are warranted to investigate pill-based delivery of green tea extracts and the optimal dose for patients with cancers (11). Too low of a dose may not prove beneficial, whereas higher doses can induce various, undesirable toxicities.

* Participants in the trial have cirrhosis; investigators are assessing if green tea extract prevents the development of liver cancer in patients.

Currently, investigators conducting clinical trials on green tea extract are evaluating its effects in patients with prostate and colon cancers. Additionally, one phase I trial is assessing the prophylactic properties of green tea catechins in cirrhotic patients.

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Resveratrol

Figure 3: Image courtesy of LivelyTable.

Resveratrol is a non-flavonoid polyphenol and phytoalexin naturally synthesized by plants in response to infections from pathogens (19). Since antiquity, both the Chinese and the Japanese have incorporated resveratrol into traditional medicines used to treat headaches and inflammation. In modern times, researchers have increasingly validated these traditional applications, noting that the substance exhibits significant antioxidant and anti-inflammatory activity. These properties have spurred renewed scientific interest in resveratrol, particularly in the context of cancer. Approximately one third of the published literature on the compound explores its use in cancers, with several investigations yielding findings that indicate that it can inhibit carcinogenesis initiation, promotion, and progression (20,21). Notably, its chemoprevention effect appears dose and duration dependent, and it may also have a synergistic effect with anticancer drugs in vitro (22). Mechanistically, resveratrol elevates expression of the anticancer protein p53 and functions as a histone deacetylase inhibitor that promotes cell cycle arrest, apoptosis, angiogenesis inhibition, and mitotic cell death in cancer cells (23).

Despite these promising findings, resveratrol has limited clinical utility because of its relatively poor bioavailability. As such, findings from cell-cultures and preclinical studies have not been reliably replicated in human clinical trials performed to date (24). To overcome this problem, researchers are exploring resveratrol in combination with bioavailability enhancers (e.g., piperine) or in other forms like micronized powders or nanotechnological formulations (20). Large doses, up to a maximum of 5 g/day, appear safe and well tolerated, but adverse events like nausea, diarrhea, and abdominal pain can occur at doses exceeding 1 g/day (25). Going forward, clarity is needed regarding optimal dosing protocols and the specific contexts in which resveratrol can counteract cancer; findings from completed human studies are summarized in Table 2. The cost for 180, 1 g capsules of resveratrol is $27.99 and can be purchased as a dietary supplement from multiple online vendors. Beyond cancer, proponents of resveratrol believe it can confer cardioprotective and neuroprotective properties, although these properties also require further validation in well-designed, adequately powered clinical trials (27).

Table 2: Clinical trials evaluating resveratrol in cancer patients. Adapted from: Ko J-H et al. Int J Mol Sci. 2017;18:2589.

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Vitamin B17 (Laetrile)

Figure 4: Image courtesy of Medical News Today.

Laetrile is a patented, intravenous form of amygdalin, which is a cyanogenic glycoside compound found naturally in the kernels of many fruits (Figure 4). First isolated in 1830 by a pair of French chemists, amygdalin has gained traction in modern times as an alternative cancer therapy (28). Multiple, in vitro studies conducted in the 2000s produced results suggesting that amygdalin can selectively induce apoptotic cancer cell death in prostate cancer, colon cancer, and promyelocytic leukemia (29,30,31). Proponents of laetrile believe that malignant cells are uniquely vulnerable to cyanogenic glycosides because they express higher levels of beta-glucosidases and beta-glucuronidase. These enzymes convert laetrile into cyanide – a highly toxic, rapidly acting mitochondrial poison that inhibits cellular respiration and promotes cell death. Another theory posits that cancer arises from deficiencies in “vitamins” like amygdalin, which is often called vitamin B17 (28). That said, there is no scientific evidence suggesting that amygdalin is actually a vitamin, despite the name (32).

Findings from a pair clinical studies conducted in the late 20th century continue to weigh heavily against the integration of laetrile into modern cancer medicine. In 1978, researchers from the National Cancer Institute (NCI) undertook a retrospective analysis in which a panel of 12 oncologists evaluated the results from 160 courses of treatment in cancer patients (68 laetrile, 68 chemotherapy, 24 no treatment). The panel judged 6 laetrile courses to have produced a response, with 2 being complete and 4 being partial (33). Later, in 1982, NCI revisited the topic by conducting a phase I/II trial. Results from this investigation indicated that oral ingestion of laetrile or amygdalin raises the risk of cyanide poisoning while failing to modify tumor growth. Only 1 of 175 evaluable patients met the criteria for a tumor response (34). This lack of efficacy, coupled with adverse events mirroring cyanide poisoning, led the U.S. Food and Drug Administration to ban laetrile, which has not been available for purchase since 1980 (35). Unless revisited and validated through well-designed clinical trials, laetrile should be avoided in patients seeking alternative therapies to treat cancer.

Stay strong, keep smiling and be your own best doctor,

- Chuck

Charles J. Meakin MD, MHA, MS

Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.

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1) Giordano A, Tommonaro G. Curcumin and cancer. Nutrients. 2019;11(10):2376.

2) Hewlings SJ, Kalman DS. Curcumin: a review of its’ effects on human health. Foods. 2017;6(10):92.

3) Lestari ML, Indrayanto G. Curcumin. Profiles Drug Subst Excip Relat Methodol. 2014;39:113-204.

4) Lao CD, Ruffin MT, Normolle D, et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006;6:10.

5) Basnet P, Skalko-Basnet N. Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules. 2011;16:4567-4598.

6) Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15:195-218.

7) Clemons R. What are the health benefits of turmeric? Choice. https://www.choice.com.au/food-and-drink/groceries/herbs-and-spices/articles/turmeric. Updated October 12, 2021. Accessed October 31, 2021.

8) Li X, Zhu X. Tea: Types, Production, and Trade. In: Caballero B, Finglas PM, Toldra F, ed. Encyclopedia of Food and Health. Academic Press; 2016: 279-282. https://www.sciencedirect.com/science/article/pii/B978012384947200684X

9) Chacko SM, Thambi PT, Kuttan R, et al. Beneficial effects of green tea: a literature review. Chin Med. 2010;5:13..

10) Wierzejska R. Tea and health – a review of the current state of knowledge. Przegl Epidemiol. 2014;68:595-599.

11) Prasanth MI, Sivamaruthi BS, Chaiyasut C, et al. A review of the role of green tea (Camellia sinensis) in antiphotoaging, stress resistance, neuroprotection, and autophagy. Nutrients. 2019;11(2):474.

12) Li F, Wang Y, Li D, et al. Perspectives on the recent developments with green tea polyphenols in drug discovery. Expert Opin Drug Discov. 2018;24:1-18.

13) Shirakami Y, Shimizu M. Possible mechanisms of green tea and its constituents against cancer. Molecules. 2018;23(9):2284.

14) Borges G, Van der Hooft JJ, Crozier A. A comprehensive evaluation of [2-(14)C](-)-epicatechin metabolome in rats. Free Radic Biol Med. 2016;99:128-138.

15) Filippini T, Malavolti M, Borrelli F, et al. Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst Rev. 2020;3(3):CD005004.

16) Yang CS, Sang S, Lambert JD. Bioavailability issues in studying the health effects of plant polyphenolic compounds. Mol Nutr Food Res. 2008;52(Suppl 1):S139-S151.

17) Hu B, Liu X, Zhang C, et al. Food macromolecule based nanodelivery systems for enhancing the bioavailability of polyphenols. J Food Drug Anal. 2017;25:3-15.

18) Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med. 2006;144:68-71.

19) Cucciolla V, Borriello A, Oliva A, et al. Resveratrol: from basic science to the clinic. Cell Cycle. 2007;6:2495-2510.

20) Singh CK, Ndiaye MA, Ahmad N. Resveratrol and cancer: challenges for clinical translation. Biochim Biophys Acta. 2015;1852(6):1178-1185.

21) Salehi B, Mishra AP, Nigam M, et al. Resveratrol: a double-edged sword in health benefits. Biomedicines. 2018;6(3):91.

22) Aluyen JK, Ton QN, Tran T, et al. Resveratrol: potential as anticancer agent. J Diet Suppl. 2012;9(1)-45-56.

23) Singh A, Bishayee A, Pandey A. Targeting histone deacetylases with natural and synthetic agents: an emerging anticancer strategy. Nutrients. 2018;10:731.

24) Ko J-H, Sethi G, Um J-Y, et al. The role resveratrol in cancer therapy. Int J Mol Sci. 2017;18:2589.

25) Patel KR, Scott E, Brown VA, et al. Clinical trials of resveratrol. Ann NY Acad Sci. 2011;1215:161-169.

26) aSquared Nutrition. 100% Natural Resveratrol – 1000 mg per serving max strength (180 capsules) antioxidant supplement, trans-resveratrol pills for heart health & pure, trans resveratrol for anti-aging. Amazon.com. https://www.amazon.com/100-Pure-Resveratrol-Antioxidant-Trans-Resveratrol/dp/B01CD3UVAK. Accessed October 30, 2021.

27) Duarte A, Martinho A, Luis A, et al. Resveratrol encapsulation with methyl-β-cyclodextrin for antibacterial and antioxidant delivery applications. Food Sci Technol. 2015;63:1254-1260.

28) Milazzo S, Horneber M, Ernst E. Laetrile treatment for cancer. Cochrane Database Syst Rev. 2015;2015(4):CD005476.

29) Chang HK, Shin MS, Yang HY, et al. Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCa prostate cancer cells. Biol Pharm Bull. 2006;29(8):1597-1602.

30) Park HJ, Yoon SH, Han LS, et al. Amygdalin inhibits genes related to cell cycle in SNU-C4 human colon cancer cells. World J Gastroenterol. 2005;11(33):5156-5161.

31) Kwon H-Y, Hong S-P, Hahn D-H, et al. Apoptosis induction of Persicae Semen extract in human promyelocytic leukemia (HL-60) cells. Arch Pharm Res. 2003;26(2):157-161.

32) Geng C, Richter A. What to know about vitamin B17. Medical News Today. https://www.medicalnewstoday.com/articles/b17-vitamin. Published July 28, 2021. Accessed October 30, 2021.

33) Ellison NM, Byar DP, Newell GR. Special report on laetrile: the NCI laetrile review. Results of the National Cancer Institute’s retrospective laetrile analysis. N Engl J Med. 1978;299(10):549-552.

34) Moertel CG, Fleming TR, Rubin J, et al. A clinical trial of amygdalin (laetrile) in the treatment of human cancer. N Engl J Med. 1982;306(4):201-206.

35) Marks J, DerSarkissian C. Is amygdalin a safe cancer treatment? WebMD. https://www.webmd.com/cancer/amygdalin-cancer-treatment/. Published October 28, 2019. Accessed October 30, 2021.