For detailed information on the studies summarised above, continue reading.
Please note this describes published clinical studies and therefore contains information of a scientific nature.
Ascorbic acid is a essential nutrient found primarily in fruits and vegetables and is a potent antioxidant. High concentrations of ascorbic acid have been shown to inhibit colon tumour progression in animal models carrying human tumours (Belin, et al. 2009), thought to be due to it's anti-proliferative activity in cancer cells. It has also been demonstrated (Catani, et al. 2002) that ascorbic acid increases the effectiveness of a class of chemotherapy drugs against cultured colon cancer cells, increasing the treated cells' sensitivity to apoptosis (preprogrammed cell death). As a antioxidant, ascorbic acid has also been shown to significantly decrease the oxidative damage that can lead to the formation of colon cancer cells (Glaab, et al. 2001).
Alpha tocopherol is a fat-soluble antioxidant found in some vegetables, eggs, milk, and some nuts. It is known to decrease the oxidative damage done to colon cells by bile acids which can lead to cancer (Rosignoli, et al. 2008). In one study (Campbell, et al. 2006), tocopherols were shown to retard growth and promote cell death in several different types of cultured colon cancer cells. Tocopherols have also been shown to anti-colon cancer activity in animal models (Ju, et al. 2009), thought to be due to their ability to induce apoptosis (preprogrammed cell death) and prevent oxidative damage and inflammation in the colon.
Selenium is an essential micronutrient for humans and is found in small amounts in nuts, cereals, meat, fish, and eggs. Selenium metabolites were shown in two studies to inhibit growth and proliferation and trigger cell death in cultured colon cancer cells (Zeng, et al. 2010; Fang, et al. 2009). In the second of these studies it in addition slowed the growth of intestinal tumours in animal models. Alpha tocopherol and selenium used together also significantly protect against oxidative damage (Bitiren, et al. 2009).
Calcium is an essential micronutrient for humans and is primarily found in dairy products such as milk and cheese, some nuts, and soy. Calcium has been shown to suppress growth and inhibit the cellular invasiveness and mobility that leads to metastasis in cultured colon cells via its direct regulation of a pivotal gene network (Bhagavathula, et al. 2007). In animal models, a "Western" diet was shown to increase the risk of and mortality from colon cancer significantly (Newmark, et al. 2009), however supplementing this diet with calcium and vitamin D significantly decreased both the incidence and multiplicity of the cancer. Calcium also increases the sensitivity of cultured colon cancer cells to certain chemotherapy drugs (Liu, et al. 2009).
Retinol is found in animal sources, including liver, dairy products, eggs, and meat, although most of these sources are also high in saturated fats and cholesterol. Retinol also inhibits the growth of multiple types of cultured colon cancer cells in a dose-dependant fashion, reducing the ability of these cells to form metastases (Park, et al. 2007). Retinol is also thought to help decrease the risk of a colon cancer as the result of a high-fat diet (Delage, et al. 2004). In one study (Ma, et al. 2009), a mix of retinol, alpha-tocopherol, and selenium inhibited colon tumour progression significantly in animal models carrying human colon tumours, slowing tumour growth compared to animals not taking the compounds. Retinol, ascorbic acid and alpha tocopherol were also shown together to increase the production of detoxifying proteins in colon cancer cells, which may be an inherent anti-cancer mechanism (Wang, et al. 1995).
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Clinical Studies Relevant To This Nutraceutical
(A brief note on "polyps": "Colonic adenomas" or "polyps", are abnormal growths of tissue that can form in the colon and eventually develop into full cancer. Because of this they are usually removed by endoscopic surgery when they are found, however they frequently grow back (or 'recur'). Therefore much research has been undertaken into the developing treatments for both these polyps and the primary cancer itself to prevent their growth or recurrence after surgery.)
Treatment of Colorectal Cancer
In one study (Roncucci, et al. 1993), the effect of treatment with retinol, ascorbic acid, and alpha-tocopherol was determined on 255 patients who had recently had surgery to have polyps removed. After an average of 18 months, only 5.7% patients taking the supplements had recurrence of polyps, versus 35.9% of patients taking no supplements. Similar results were shown in a second study (McKeown-Eyssen, et al. 1988), in which 200 patients were given ascorbic acid and alpha tocopherol after surgery to remove polyps. After two years, polyps were observed in 20% less patients taking the supplements compared to those patients taking a placebo only. These results are in contrast to a third study (Greenberg, et al. 1994), however, in which patients who had polyps recently removed were given ascorbic acid and alpha tocopherol every day for 4 years, and in these patients there was no significant benefit to the treatment. This reason for the discrepancy in this earlier study is not clear, however it may be due to the different doses of ascorbic acid and alpha tocopherol used in this study compared to the other studies.
In another small study (Malmberg, et al. 2002), short-term treatments of alpha tocopherol, ascorbic acid, and selenium was given to patients with advanced colorectal cancer, which significantly boosted the functioning of their immune system, which is often weakened in these patients and can result in increased susceptibility to infection and disease progression. In a fifth study (Cascinu, et al. 2000), colorectal cancer patients were treated with retinol, ascorbic acid, alpha tocopherol, and calcium to investigate the effects on the proliferation of cells around the site of the tumour. After 6 months of treatment, there was a significant decrease in the proliferation of these cells in patients treated with both the supplements and a placebo treatment, however while there was a larger decrease in the patients treated with supplements, this did not reach statistical significance. In another study (Fedirko, et al. 2009) 92 patients with polyps who were given calcium together with Vitamin D for 6 months showed an increase in markers of cell death in samples of their colon tissue. Finally, in a seventh study (Hofstad, et al. 1998), 116 patients with polyps were given a treatment which included ascorbic acid, alpha tocopherol, selenium, and calcium, or a placebo, to determine it's effect on polyp growth or recurrence. After 3 years of supplement use, there was a significant decrease in the number of new polyps formed in those patients taking the supplements, and in addition the growth rate of polyps specifically in patients less than 60 years of age was significantly decreased.
Prevention of Colorectal Cancer
While some studies have shown that these supplements can have a positive effect on the prevention of colorectal cancer (as opposed to the treatment of colorectal cancer outlined above), the evidence is currently inconsistent and somewhat weak.
Other Known Effects
Retinol, ascorbic acid, alpha tocopherol, calcium, and selenium are important micronutrients required by humans, and have a range of other important roles in the body.
Retinol is important for healthy eyesight, and required for both scotopic and colour vision. It is also important for maintaining healthy teeth, skeletal and soft tissue, mucous membranes, and skin. As an antioxidant, it protects cells from free radicals and the degenerative processes seen in aging. Retinol is also important for maintaining a strong immune system.
Ascorbic acid is required for a range of essential metabolic reactions, and is a strong antioxidant. Antioxidants neutralize free radicals, thereby preventing oxidative stress which can cause cardiovascular diseases, hypertension, chronic inflammatory diseases and diabetes, among other things. Some scientific evidence also suggests it has a beneficial role on the immune system, asthma, ischemic heart disease, and stroke prevention, however further work is ongoing to determine this conclusively.
Alpha tocopherol is also an important antioxidant with many functions within the body. Deficiency of alpha tocopherol can lead to neurological problems and anaemia. There is some limited evidence that alpha tocopherol may protect against Parkinson's disease, glaucoma, and blood clots, and when combined with other antioxidants such as ascorbic acid, may be protective against age-related macular degeneration.
Selenium is important for the normal functioning of the thyroid gland. Deficiencies in selenium can result in heart abnormalities and degeneration of cartilage tissue. There is also some weak evidence to suggest that it may decrease the risk of diabetes.
Calcium is an essential mineral for humans and is the most plentiful mineral found in the human body. It is important for the maintenance of strong teeth and bones, and for preventing osteoporosis. It is also needed for effective blood clotting, nerve signalling, and muscle contraction, including that of a healthy heart.
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We would highly recommend that anyone interested in researching these nutritional supplements or prostate cancer further look at the main database of scientific and clinical studies, PubMed. It is free to search and view abstracts from millions of scientific studies published in peer-reviewed scientific journals over the past several decades. Full tutorials and help using PubMed can be found here. While they are generally of a technical nature and intended for a scientific/medical professional audience, non-specialists should also find them extremely useful.
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Malmberg KJ, Lenkei R, Petersson M, Ohlum T, Ichihara F, Glimelius B, Frödin JE, Masucci G, Kiessling R. Clin Cancer Res. 2002 Jun;8(6):1772-8. A short-term dietary supplementation of high doses of vitamin E increases T helper 1 cytokine production in patients with advanced colorectal cancer.
Cascinu S, Ligi M, Del Ferro E, Foglietti G, Cioccolini P, Staccioli MP, Carnevali A, Luigi Rocchi MB, Alessandroni P, Giordani P, Catalano V, Polizzi V, Agostinelli R, Muretto P, Catalano G. Cancer Invest. 2000;18(5):411-6. Effects of calcium and vitamin supplementation on colon cell proliferation in colorectal cancer.
Albanes D, Malila N, Taylor PR, Huttunen JK, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Barrett MJ, Pietinen P, Hartman TJ, Sipponen P, Lewin K, Teerenhovi L, Hietanen P, Tangrea JA, Virtanen M, Heinonen OP. Cancer Causes Control. 2000 Mar;11(3):197-205. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland)
Hofstad B, Almendingen K, Vatn M, Andersen SN, Owen RW, Larsen S, Osnes M. Digestion. 1998;59(2):148-56. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants.
Roncucci L, Di Donato P, Carati L, Ferrari A, Perini M, Bertoni G, Bedogni G, Paris B, Svanoni F, Girola M, et al. Dis Colon Rectum. 1993 Mar;36(3):227-34. Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas. Colorectal Cancer Study Group of the University of Modena and the Health Care District 16.
McKeown-Eyssen G, Holloway C, Jazmaji V, Bright-See E, Dion P, Bruce WR. Cancer Res. 1988 Aug 15;48(16):4701-5. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps.
Greenberg ER, Baron JA, Tosteson TD, Freeman DH Jr, Beck GJ, Bond JH, Colacchio TA, Coller JA, Frankl HD, Haile RW, et al. N Engl J Med. 1994 Jul 21;331(3):141-7. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group.
Belin S, Kaya F, Duisit G, Giacometti S, Ciccolini J, Fontés M. PLoS One. 2009;4(2):e4409. Epub 2009 Feb 6. Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression.
Park EY, Wilder ET, Lane MA. Nutr Cancer. 2007;57(1):66-77. Retinol inhibits the invasion of retinoic acid-resistant colon cancer cells in vitro and decreases matrix metalloproteinase mRNA, protein, and activity levels.
Catani MV, Costanzo A, Savini I, Levrero M, de Laurenzi V, Wang JY, Melino G, Avigliano L. Biochem J. 2002 Jun 1;364(Pt 2):441-7. Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: implications for the cellular response to DNA damage.
Glaab WE, Hill RB, Skopek TR. Carcinogenesis. 2001 Oct;22(10):1709-13. Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells.
Ma H, Das T, Pereira S, Yang Z, Zhao M, Mukerji P, Hoffman RM. Anticancer Res. 2009 Jul;29(7):2421-6. Efficacy of dietary antioxidants combined with a chemotherapeutic agent on human colon cancer progression in a fluorescent orthotopic mouse model.
Delage B, Groubet R, Pallet V, Bairras C, Higueret P, Cassand P. Nutr Cancer. 2004;48(1):28-36. Vitamin A prevents high fat diet-induced ACF development and modifies the pattern of expression of peroxisome proliferator and retinoic acid receptor m-RNA.
Ju J, Hao X, Lee MJ, Lambert JD, Lu G, Xiao H, Newmark HL, Yang CS. Cancer Prev Res (Phila Pa). 2009 Feb;2(2):143-52. Epub 2009 Jan 20. A gamma-tocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice.
Campbell SE, Stone WL, Lee S, Whaley S, Yang H, Qui M, Goforth P, Sherman D, McHaffie D, Krishnan K. BMC Cancer. 2006 Jan 17;6:13. Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines.
Zeng H, Botnen JH, Briske-Anderson M. Nutr Cancer. 2010;62(1):85-92. Deoxycholic acid and selenium metabolite methylselenol exert common and distinct effects on cell cycle, apoptosis, and MAP kinase pathway in HCT116 human colon cancer cells.
Fang W, Han A, Bi X, Xiong B, Yang W. Int J Cancer. 2009 Nov 10. Tumour inhibition by sodium selenite is associated with activation of c-Jun NH2-terminal kinase 1 and suppression of beta-catenin signaling.
Bitiren M, Karakilcik AZ, Zerin M, Ozardalı I, Selek S, Nazlıgül Y, Ozgonul A, Musa D, Uzunkoy A. Biol Trace Elem Res. 2009 Sep 23. Protective Effects of Selenium and Vitamin E Combination on Experimental Colitis in Blood Plasma and Colon of Rats.
Fedirko V, Bostick RM, Flanders WD, Long Q, Shaukat A, Rutherford RE, Daniel CR, Cohen V, Dash C. Cancer Prev Res (Phila Pa). 2009 Mar;2(3):213-23. Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical trial.
Newmark HL, Yang K, Kurihara N, Fan K, Augenlicht LH, Lipkin M. Carcinogenesis. 2009 Jan;30(1):88-92. Epub 2008 Nov 18. Western-style diet-induced colonic tumours and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer.
Liu G, Hu X, Varani J, Chakrabarty S. Mol Carcinog. 2009 Mar;48(3):202-11. Calcium and calcium sensing receptor modulates the expression of thymidylate synthase, NAD(P)H:quinone oxidoreductase 1 and survivin in human colon carcinoma cells: promotion of cytotoxic response to mitomycin C and fluorouracil.
Bhagavathula N, Hanosh AW, Nerusu KC, Appelman H, Chakrabarty S, Varani J. Int J Cancer. 2007 Oct 1;121(7):1455-62. Regulation of E-cadherin and beta-catenin by Ca2+ in colon carcinoma is dependent on calcium-sensing receptor expression and function.
Wang W, Higuchi CM. Cancer Lett. 1995 Nov 27;98(1):63-9. Induction of NAD(P)H:quinone reductase by vitamins A, E and C in Colo205 colon cancer cells.
Rosignoli P, Fabiani R, De Bartolomeo A, Fuccelli R, Pelli MA, Morozzi G. Genotoxic effect of bile acids on human normal and tumour colon cells and protection by dietary antioxidants and butyrate. Eur J Nutr. 2008 Sep;47(6):301-9. Epub 2008 Aug 6.