Nutraceuticals to combat cancer

Regulations keep marketers from selling supplements for the dreaded 'C' word. But science marches on. Mark J Tallon, PhD, keeps tabs on the proliferating state of nutritional cancer-related research from the vitamin, peptide and botanical-research vault

The impact of cancer continues to be one of the greatest medical burdens in the world, despite countless pharmaceutical offerings. With fatalities from cancer accounting for more than 13 per cent of all deaths worldwide, and one in four within the UK and the US, the search for efficacious treatments and therapies have never been so urgent. The treatment of cancer patients carries a $280 billion price tag. Any impact the natural-products industry can offer toward prevention is welcome relief to the struggling economies of the world — not to mention the more than 12 million newly diagnosed cancer patients this year.

Despite the huge spend on cancer treatment, it has been shown that many cancer forms are preventable through lifestyle choices. Choices such as smoking cessation, exercise and healthier diets could cut the incidence of cancer worldwide by 40 per cent, Despite our vast understanding of the aetiology of cancers, and the processes by which they attack the body, the nutritional literature is fraught with contradiction and subjection.

Such research can be divided into three distinct nutritional applications: prevention (pre-diagnosis), treatment (following diagnosis) and rehabilitation (post surgical and pharmaceutical intervention). Vitamin D and soy reduce risk, flax may slow proliferation, green tea may decrease the number and size of polyps, and glutamine reduces side effects of chemo. The following provide insight into these ingredients, targeting these phases and the ingredients' place in the wider nutraceuticals market.

How high the D dose?
The vitamin D receptor (VDR) has been hot news in the vitamin world since 1981 when research demonstrated vitamin D3 could inhibit human melanoma-cell proliferation at nanomolar concentrations. The use of vitamin D to activate the VDR may have problems because it can directly influence calcium absorption, which carries the potential of hypercalcaemia. Despite more than 150 studies linking VDR to cancer progression, very few long-term human intervention trials have been conducted.

Following some excellent review work, researchers from Creighton University carried out the first double-blind, placebo-controlled trial to assess the supplemental intake of vitamin D and calcium on cancer incidence over a four-year period. The study was conducted on 1,180 post-menopausal women. The outcome showed that improving vitamin D status substantially reduced all cancer risk in postmenopausal women. Furthermore, baseline and serum concentrations of vitamin D (Serum 25(OH)D) were also found to be strong predictors of cancer risk, which is in line with previous epidemiological work.

Just as we think we are onto a big winner with vitamin D, the results of the Women's Health Initiative (WHI) on supplementation with vitamin D+calcium were released. The results of the study pointed out that supplementation did not have a statistically significant effect on mortality rates. However, there are a few caveats to what brought some bad publicity for vitamin D market. First, the authors of the WHI trial stated, "Findings support the possibility that these supplements may reduce mortality rates in postmenopausal women." Second, the dose was significantly different from the 2007 Lappe trial, which gave 1,100IU vs the WHI study, which provided only 400IU of vitamin D3.

Given the correlation between serum vitamin D levels, reduced mortality and cancer incidence, the results of the WHI are not unexpected and provide more information toward increasing the level of circulating vitamin D to afford a therapeutic effect. The take home of these trials is that the Lappe trial led to a reduced cancer development of almost 50 per cent.

As research develops further for vitamin D and cancer, the focus must be on defining the optimal level of serum vitamin D and the potential of commercialising in-store blood vitamin D testing systems (as available for cholesterol and blood glucose). Current theories suggest the mechanism of prevention provided by vitamin D supplementation is via enabling better signalling between healthy cells, which allows better cell turnover. Lead researcher in the field, Cedric Garland of UC San Diego School of Medicine, commented, "Diet and supplements can restore appropriate vitamin D levels, and perhaps help in preventing cancer development. Vitamin D levels can be increased by modest supplementation with Vitamin D3 in the range of 2,000IU/day."

New soy sense
The application of soy in heart and bone health post-menopause is well known, but its applications to cancer are still emerging within the scientific community. In a 2009 study from the Vanderbilt University School of Medicine (USA), researchers assessed the impact of soy as a rich source of isoflavones and its potential as an anticarcinogenic intervention.

The study objective was to evaluate the relationship of adolescent and adult soy-food intake with breast-cancer risk in a cohort of 73,223 Chinese women. A validated food-frequency questionnaire was used to assess usual dietary intake during adulthood and adolescence, with follow-up assessment at 7.4 years.

Results from the trial demonstrated that adult soy consumption, measured either by soy-protein or isoflavone intake, was inversely associated with the risk of premenopausal breast cancer. Similarly, high intake of soy foods during adolescence was also associated with a reduced risk of premenopausal breast cancer.

Although not a direct intervention trial and with the potential for many confounding variables, this large, population-based, prospective cohort trial still provides strong evidence of a protective effect of soy-food intake. One of the most interesting applications of this trial is its position as a premenopausal (as opposed to the usual post-menopausal soy trials) breast-cancer protectant irrespective of isoflavone contents.

Flaxseed slows proliferation
Flaxseed is a concentrated source of omega-3s. A recent trial conducted at the University of Texas assessed the effects of a low-fat and /or flaxseed diet on the progression and development of prostate cancer. Prostate cancer patients (n=161) scheduled at least 21 days before prostatectomy were randomly assigned to one of four groups: control (usual diet), 30g/day flaxseed-supplemented diet, low-fat diet (<20% total energy), or a flaxseed—supplemented, low—fat diet for 30 days.

Proliferation rates of cancer cells were significantly lower among men assigned to the flaxseed groups. No differences were observed between groups with regard to side effects, apoptosis and most serologic endpoints; however, men on low-fat diets experienced significant decreases in serum cholesterol. These findings suggest that flaxseed is safe and associated with biological alterations that may be protective for prostate cancer.

Green tea chemoprotects
Green tea has been a traditional beverage in Japan for many years. During the past decade it has gained significant market traction with Western consumers. Epidemiological studies have indicated an intake of green tea above 10 cups per day reduces the risk of colorectal cancer. In the latest research on green tea extract (GTE), researchers assessed its efficacy as a protective agent against cancer.

Researchers from Japan conducted a randomised trial on 136 patients (65 control, 71 GTE) to determine the preventive effect of GTE supplements on colorectal adenomas by increasing green tea consumption from an average of six cups (1.5 g GTE) daily to > or = 10 cups equivalent (2.5 g GTE) by supplementing with GTE tablets. The efficacy of the intervention was assessed by monitoring the number of adenomas (polyps) present pre and one-year post supplementation.

Results showed that the incidence of adenomas at the one-year colonoscopy was significantly lower in the GTE group (15 per cent) compared to those in the control (31 per cent). Additionally, the size of relapsed adenomas was also smaller in the GTE group than in the control group.

These results demonstrate that GTE is an effective supplement for preventing colorectal adenomas. Research in this form of cancer is a definite growth area, with recent trials on folic acid and B6 intake showing significant benefits on colorectal adenomas and cancer incidence.

Glutamine weighs in
As one of the most abundant peptides in the body, glutamine has been the focus of nutritional support for many years. The research focus for glutamine has been on burn victims, as fuel for mucosal cells, and also as a rehydration ingredient. However, in relation to cancer, glutamine's beneficial effect on immune function became the focus of researchers at Thailand's Chiangmai University in late 2008.

In a pilot study, researchers examined the ability of glutamine to reduce the side effects of chemotherapy in patients suffering from acute myeloid leukaemia (AML). Sixteen AML patients were randomised to receive intravenous supplementation with glutamine (30g/day) or an equivalent quantity (25g/day) of a standard amino acid mixture (control) on days 1-5 of chemotherapy.

In glutamine-treated patients, the percentage of neutrophil phagocytosis (white blood cell destruction) and superoxide anion (free radical) generation was significantly higher than in control patients. Interestingly, the glutamine-treated patients also lost significantly less weight, a significant factor in cancer mortality rates. They also tended to have shorter in-patient duration, and had less-severe oral mucositis (inflammation and ulceration of the digestive tract) than controls. This reduction in mucositis may have which helped with weight gain due to better feeding habits.

Although this was only a small-scale trial, the data positively shows a significant enhancement in neutrophil phagocytic function, maintenance in nutritional status and body weight, as well as being cost effective. Although initial implications are positive, further studies involving more patients need to be undertaken to confirm the results of this trial. In addition, the method of delivery or administration of the glutamine to study participants needs to be orally ingested for the science to apply for consumer glutamine products.

Another 'C'-word: caution
Despite a number of significant trials using nutraceuticals for preventing or treating symptoms relating to cancer, marketing such effects or nutrients is very difficult if not downright illegal. In most Western countries, any "disease, treat or cure" claims in relation to cancer would be defined as medicinal or a drug. As such a medicine's authorisation would be required for any such product. This is significant and probably too great an investment for most large nutrition or food manufacturers. The future for such products within medical nutrition is unclear and may form the role of pharma support, as with glutamine. Pure nonpharma, nonmedical, combination commercial applications are some way off at this time.



Selenium: The ongoing controversy
Everybody knows selenium is a potent antioxidant — it's a staple of the ACES antioxidant formulations that also contain vitamins A, C and E.

But can it prevent prostate cancer? A 1996 JAMA study found it reduced colon, lung and prostate cancers by between 50 and 63 per cent. This led to a 2003 FDA-minted qualified health claim for selenium and prostate cancer. But a 2009 JAMA paper said selenium had no effect on prostate health — indeed, the so—called SELECT study was stopped short because there was a slight, nonsignificant increase in diabetes incidence in the selenium group.

The Center for Science in the Public Interest — no fan of the supplements industry — used the JAMA paper as a cause celebre to sue Bayer HealthCare for its One-A-Day Men's Health Formula because it makes claims about prostate cancer due to its selenium ingredient. CSPI has also petitioned FDA to pull Bayer's products from the shelves, calling selenium products "dangerous to the health of men."

The Council for Responsible Nutrition joined the fray in July, CEO Steven Mister calling CSPI's actions "an unfortunate turn of events" and blasting the consumer-advocacy group's shoddy rationale, sniffing, "an organization that even has 'science' in its name."

The FDA did take notice of the latest JAMA paper, however, amending the qualified health claim in a way to make marketers cringe, to wit:

"Two weak studies suggest that selenium intake may reduce the risk of prostate cancer. However, four stronger studies and three weak studies showed no reduction in risk. Based on these studies, FDA concludes that it is highly unlikely that selenium supplements reduce the risk of prostate cancer."

Barking up the wrong tree?
As too often happens, lost in the headlines and recriminations is the truth of the matter: Form equals function. In the selenium saga, the original 1996 study used high-selenium yeast, which is different from the selenomethionine used in the 2009 SELECT study or, for that matter, the selenate form in the Bayer product.

"They used the wrong selenium form. Form is the key," asserted Mark Whitacre, PhD, chief operating officer for Cypress Systems, supplier of SelenoExcell high-selenium yeast. "The qualified health claims says that more research needs to be done. We think it's exactly where it needs to be.

Whitacre, who received his PhD in selenium chemistry from Cornell University in 1983, explained that the most likely reason high-selenium yeast has been shown to be more effective for cancer prevention is because other forms of selenium compounds exist in high-selenium yeast other than selenomethionine, and all of them are organically bound to proteins in the yeast that protect the selenium from oxidation.

He guessed that one reason the National Cancer Institute chose selenomethionine over high—selenium yeast is precisely because selenomethionine is well defined, with only one free compound, vs the multiple organically bound compounds in the high-selenium yeast.

"We suspect that the advantage of high-selenium yeast lies in its content of multiple forms of selenium, including some forms that are more effective than selenomethionine in anti—carcinogenesis," he said.

Previous animal studies have shown no effect with selenomethionine, validating the SELECT findings.

Cypress Systems has about ten studies currently under way, with the most compelling one a double-blind, placebo-controlled human clinical comparing the maligned selenomethionine with the high-selenium yeast version.

"If form does make a difference, that study will show it," said Whitacre. "We're four or five years off from getting the results."

In the meantime, selenium is still undisputed as an antioxidant and will continue to find a home in antioxidant formulations.

"Manufacturers like the (cancer) attribute, but they really market it as an antioxidant," said Whitacre. And to that end, Cypress in March received an FDA letter of no objection for GRAS for its selenium. Look for it in cereals and bars.

—Todd Runestad


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