Vitamin D and Your Health Cancer
Vitamin D and Prostate Cancer
Prostate cancer kills 31,000 American men every year, the second leading cause of cancer deaths among men. This year, more than 220,000 American men will be diagnosed with the disease, making prostate cancer the leading cancer among men. Early diagnosis is important as surgery can be curative. After the cancer has spread, especially to bone, treatment options are more limited. Castration, usually chemical, will delay the cancer from spreading for several years, but then the treatment options are quite limited.
Many experts will tell you that vitamin D should not be taken for prostate cancer until well-controlled scientific studies prove it helps. The problem with that approach is two-fold. First, a person may die waiting for the studies to be conducted and two, it misses the point. The point is this: men with prostate cancer should not allow themselves to be vitamin D deficient and neither should their doctors.
If you have prostate cancer, please remember that we still have a lot to learn about vitamin D and it should not be considered as the main treatment for your cancer. Your oncologist will prescribe treatment that has proven efficacy and you should carefully follow their advice as the mainstay of treatment. At the same time, you should know that evidence suggests that the proper amount of vitamin D3 may help you in your fight against prostate cancer.
Vitamin D In the Fight Against Prostate Cancer
Let us look at selected studies from the scientific literature to see what clues exist about the role vitamin D may play in preventing and treating prostate cancer.
In 1990, Schwartz proposed that vitamin D deficiency may underlie the major risk factors for prostate cancer including age, black race, and northern latitudes. He pointed out that all these factors are associated with decreased synthesis of vitamin D. Mortality rates from prostate cancer in the U.S. are inversely correlated with ultraviolet radiation, the principal source of vitamin D. Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer?(Hypothesis). Anticancer Res. 1990 Sep–Oct;10(5A):1307–11.
Sunlight and Vitamin D
In 1992, Hanchette and Schwartz again proposed that sunlight and vitamin D may play a role in prostate cancer. They pointed out that men in the United States were 10 times more likely to develop prostate cancer than men in Japan, where men consume higher amounts of vitamin D due to their consumption of fatty fish. Although the authors did not mention it, Japanese men also consume soy, which inhibits the breakdown of calcitriol (activated vitamin D) in the tissues. Furthermore, traditional Japanese men consume higher quantities of omega-3 fatty acids than their American counterparts. These fats are now known to dissociate vitamin D metabolites from their binding protein, thus raising active levels of those metabolites in the blood.
To support their hypothesis, Hanchette and Schwartz analyzed American prostate cancer deaths in relation to sunlight and discovered a 0.0001 negative correlation—what is a very significant association. That is, they found that men who received more sunlight were less likely to die from prostate cancer. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer. 1992 Dec 15;70(12):2861–9.
In the same year, Schwartz discovered that death rates from prostate cancer were correlated with death rates from multiple sclerosis, another disease know to be associated with lack of sunlight. Again, he proposed that lack of vitamin D may a causative factor in both diseases. Schwartz GG. Multiple sclerosis and prostate cancer: what do their similar geographies suggest? Neuroepidemiology. 1992;11(4–6):244–54.
In 1993, Skowronski and colleagues discovered that all three of the prostate cancer cell lines they studied possessed a vitamin D receptor and that the active form of vitamin D, calcitriol, "dramatically inhibited" the growth of two of the three cell lines. Skowronski RJ, Peehl DM, Feldman D. Vitamin D and prostate cancer: 1,25 dihydroxyvitamin D3 receptors and actions in human prostate cancer cell lines. Endocrinology. 1993 May;132(5):1952–60.
Over the next several years, four studies appeared to disprove the vitamin D hypothesis. In each case, various metabolites of vitamin D were drawn on large numbers of men who were then followed over many years to see which men developed prostate cancer. Although some of the studies found that activated vitamin D (calcitriol) levels in the blood protected against colon cancer, none of the studies showed that low calcidiol levels (25-hydroxyvitamin D) were associated with risk of developing prostate cancer. Schwartz's hypothesis appeared to be disproved. Corder EH, Guess HA, Hulka BS, Friedman GD, Sadler M, Vollmer RT, Lobaugh B, Drezner MK, Vogelman JH, Orentreich N. Vitamin D and prostate cancer: a prediagnostic study with stored sera. Cancer Epidemiol Biomarkers Prev. 1993 Sep–Oct;2(5):467–72. Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States) Cancer Causes Control. 1995 May;6(3):235–9. Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG, Stampfer MJ. Circulating vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer Epidemiol Biomarkers Prev. 1996 Feb;5(2):121–6. Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, Turner A, Holick MF. Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States) Cancer Causes Control. 1998 Aug;9(4):425–32.
However, in 1995 Miller and colleagues expanded their earlier work and examined seven prostate cancer cell lines. They found all 7 lines had receptors for vitamin D. They also showed that activated vitamin D (calcitriol) inhibited the growth of four of seven prostatic carcinoma cell lines and found that the more vitamin D receptors, the greater the inhibition. Furthermore, they found that the enzyme that breaks down calcitriol in the tissues (24-hydoxylase) reduced that inhibition. That is, the more 24-hydroxylase, the less the cancer cells were inhibited by activated vitamin D. Not only did this mean that activated vitamin D may retard prostate cancer growth, it suggested that substances which interfere with 24-hydroxylase may also prove useful in treating prostate cancer. Miller GJ, Stapleton GE, Hedlund TE, Moffat KA. Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1alpha,25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines. Clin Cancer Res. 1995 Sep;1(9):997–1003.
Vitamin D Acknowledged
Later in 1995, Feldman and colleagues at Stanford University confirmed Miller's findings and stated, "Based on these findings, we postulate that vitamin D may have protective actions on the development and/or progression of prostate cancer...We further hypothesize that vitamin D supplementation may have beneficial effects on retarding the development and/or progression of prostate cancer." For the first time, cancer researchers at a major university seemed to be saying that evidence existed that cholecalciferol (plain vitamin D3) may be useful in preventing and treating prostate cancer. Feldman D, Skowronski RJ, Peehl DM. Vitamin D and prostate cancer. Adv Exp Med Biol. 1995;375:53–63.
In 1998, Gross and colleagues at Stanford conducted the first clinical trial of a vitamin D metabolite in treating advanced prostate cancer. However, instead of raising the tissue levels of activated vitamin D (calcitriol) by supplementing with oral vitamin D (cholecalciferol), they chose to give calcitriol itself. In spite of circumventing the natural system to raise prostate calcitriol levels, they found calcitriol decreased the rate of progression of PSA blood levels (a test of prostate cancer's progression) in 6 of the 7 patients. Elevations in blood calcium levels (hypercalcemia) seriously limited the use of calcitriol and the cancer eventually progressed. (No one knows what would have happened to those 7 men if they had been given equipotent doses of vitamin D3 cholecalciferol. Cholecalciferol has to be given in massive doses (40,000 units) over an extended period of time (months) to cause significant hypercalcemia. In addition, the tissue production of calcitriol is not rate limited, suggesting that oral cholecalciferol is effective in raising tissue levels of calcitriol. Gross C, Stamey T, Hancock S, Feldman D. Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol) J Urol. 1998 Jun;159(6):2035–9.
In 1998, Schwartz, the same scientist who had first postulated that vitamin D deficiency played a role in prostate cancer, confirmed that prostate cells, including most prostate cancer cell lines, were able to activate vitamin D. Schwartz and his colleagues concluded that "these data suggest a potential role for 25(OH)D (calcidiol) in the chemoprevention of invasive prostate cancer." As the easiest way to raise calcidiol is through oral supplementation with vitamin D3, this meant scientists at another major American medical school were suggesting that plain, inexpensive, non-prescription vitamin D may help prostate cancer. Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF. Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev. 1998 May;7(5):391–5.
In the year 2000, Ahonen and colleagues conducted a careful study of calcidiol levels in young men and followed them for the development of prostate cancer. Unlike earlier studies, he found a relationship between low vitamin D blood levels and prostate cancer. Ahonen found young men with calcidiol levels below 40 nmol/L (16 ng/mL) were three times more likely to develop prostate cancer than were men with higher levels.
Just as important, he found these men were 6 times more likely to develop invasive cancers. This finding implied a treatment effect for vitamin D as the prevention of invasiveness is a key goal of treatment. Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control. 2000 Oct;11(9):847–52.
Later in 2000, Barreto and colleagues at Wake Forest University School of Medicine were the first see if calcidiol inhibited prostate cell growth. They found that calcidiol was just as effective as calcitriol in inhibiting growth. The concluded that their findings "support the use of 25(OH)D as a chemotherapeutic agent in the treatment of prostate cancer." As oral cholecalciferol is the best way to raise calcidiol levels, it became clear that another group of cancer researchers at a major university medical center was calling for the use of vitamin D in prostate cancer. Barreto AM, Schwartz GG, Woodruff R, Cramer SD. 25-Hydroxyvitamin D3, the prohormone of 1,25-dihydroxyvitamin D3, inhibits the proliferation of primary prostatic epithelial cells. Cancer Epidemiol Biomarkers Prev. 2000 Mar;9(3):265–70.
Chen and colleagues at Boston University School of Medicine then demonstrated that calcidiol was just as effective as calcitriol in inhibiting growth of prostate cancer cell lines in the test tube. They also found that a vitamin D analogue already on the market, one known to cause less hypercalcemia than other analogues (patentable modifications of calcitriol), was also effective in inhibiting cancer growth. However, their findings about calcidiol again emphasized that readily available vitamin D should help fight prostate cancer. In fact, the authors concluded calcidiol might be a good candidate for "human trials in prostate cancer." Now 4 different groups of scientists, from 4 major university medical centers, were calling for the use of vitamin D in prostate cancer. Chen TC, Schwartz GG, Burnstein KL, Lokeshwar BL, Holick MF. The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. Clin Cancer Res. 2000 Mar;6(3):901–8.
Sun Exposure, Skin Type, and Reduced Risk
In 2001, Luscombe and colleagues at the School of Medicine in North Straffordshire Hospital in England published three studies linking ultraviolet exposure and skin type to the development of prostate cancer. They found that cumulative outdoor exposure, outdoor occupations and skin type was associated with reduced risk of advanced stage tumors. They also found that childhood sunburns dramatically reduced the risk of developing prostate cancer, probably because those with fair skin are more likely to burn but also find it easier to make vitamin D in their skin. Furthermore, they found that people who have difficulty making the skin pigment melanin (a natural sunscreen) are much less likely to develop prostate cancer. Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Fryer AA, Strange RC. Prostate cancer risk: associations with ultraviolet radiation, tyrosinase and melanocortin-1 receptor genotypes. Br J Cancer. 2001 Nov 16;85(10):1504–9. Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Fryer AA, Strange RC. Outcome in prostate cancer associations with skin type and polymorphism in pigmentation-related genes. Carcinogenesis. 2001 Sep;22(9):1343–7. Luscombe CJ, Fryer AA, French ME, Liu S, Saxby MF, Jones PW, Strange RC. Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer. Lancet. 2001 Aug 25;358(9282):641–2.
In addition, in 2001 Zhao and Feldman at Stanford University studied the one prostate cancer cell line, DU 145, that does not respond to calcitriol. They found this cell line, which is poorly differentiated and derived from brain metastasis, can be made to respond to calcitriol by adding drugs which inhibit the breakdown of calcitriol. This raised the possibility that prostate cancers which did not respond to vitamin D could be made responsive by the addition of a metabolic inhibitor. Farhan and colleagues at the University of Vienna Medical School soon showed that the isoflavonoid found in soybeans, called genistein, is a powerful metabolic inhibitor of the enzyme that breaks down calcitriol. Zhao XY, Feldman D. The role of vitamin D in prostate cancer. Steroids. 2001 Mar–May;66(3–5):293–300. Farhan H, Wahala K, Adlercreutz H, Cross HS. Isoflavonoids inhibit catabolism of vitamin D in prostate cancer cells. J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Sep 25;777(1–2):261–8.
In 2003, Chen and Holick at Boston University School of Medicine reiterated their call for the use of vitamin D in prostate cancer. After reviewing most of the research on the subject, the authors concluded, "adequate exposure to sunlight or oral supplementation might provide a simple way to increase synthesis of calcitriol in the prostate and, therefore, decrease the risk of prostate cancer." They added, "adequate vitamin D nutrition should be maintained, not only for bone health in men and women, but because it might decrease the risk of prostate cancer and mitigate metastatic disease should it develop." Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends Endocrinol Metab. 2003 Nov;14(9):423–30.
In 2003, Bodiwala and colleagues in England studied sun exposure and skin type and again found that men who sunbathed or otherwise exposed themselves to sunlight were less likely to develop prostate cancer. They also identified men with various combinations of skin type and reduced sun exposure, which were up to 13 times more likely to develop prostate cancer. Bodiwala D, Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Fryer AA, Strange RC. Associations between prostate cancer susceptibility and parameters of exposure to ultraviolet radiation. Cancer Lett. 2003 Oct 28;200(2):141–8. Bodiwala D, Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Ramachandran S, Fryer AA, Strange RC. Susceptibility to prostate cancer: studies on interactions between UVR exposure and skin type. Carcinogenesis. 2003 Apr;24(4):711–7. Bodiwala D, Luscombe CJ, Liu S, Saxby M, French M, Jones PW, Fryer AA, Strange RC. Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight. Cancer Lett. 2003 Mar 31;192(2):145–9.
Also in 2003, Beer and colleagues at the Oregon Health and Science University again tested calcitriol as a treatment for prostate cancer. They found a significant reduction in the rate of increase in PSA, a marker of the cancer's growth, although no patient achieved the hoped for 50% reduction. Unfortunately, none of the patients received oral vitamin D supplementation, which would have been more effective in raising prostate calcitriol levels. In fact, none of the patients were even tested or treated for vitamin D deficiency. Beer TM, Lemmon D, Lowe BA, Henner WD. High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer. 2003 Mar 1;97(5):1217–24.
Calcitriol Breakdown Reduced by Soy Isoflavonoids
In 2003, two studies from at the University of Vienna Medical School confirmed that the isoflavonoids in soy dramatically reduce the breakdown of calcitriol in prostate cancer cells. In fact, they found that such products profoundly inhibit the enzyme that metabolizes calcitriol, reducing its activity to almost zero. This again raised the possibility that such compounds could be combined with vitamin D to treat prostate cancer. Cross HS, Kallay E, Farhan H, Weiland T, Manhardt T. Regulation of extrarenal vitamin D metabolism as a tool for colon and prostate cancer prevention. Recent Results Cancer Res. 2003;164:413–25. Farhan H, Wahala K, Cross HS. Genistein inhibits vitamin D hydroxylases CYP24 and CYP27B1 expression in prostate cells. J Steroid Biochem Mol Biol. 2003 Mar;84(4):423–9. Cross HS, Kallay E, Lechner D, Gerdenitsch W, Adlercreutz H, Armbrecht HJ. Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. J Nutr. 2004 May;134(5):1207S–1212S.
Three studies in 2004 examined the association between vitamin D levels and prostate cancer. Two of the studies found no association between vitamin D levels and the subsequent risk of developing prostate cancer. A third study from Finland actually raised the possibility that both low and high vitamin D levels are associated with prostate cancer.
Tissue Calcidiol Levels
Careful analysis of the Finnish paper revealed 57 of the 67 men with high vitamin D blood levels who subsequently developed prostate cancer were from Norway. In Norway, increased consumption of vitamin A (associated with increased risk of prostate cancer) through cod liver oil is common.
In addition, in a letter to the editor, Reinhold Vieth proposed that the Finnish finding was best explained by annual variations in calcidiol levels causing low tissue calcitriol levels. In their response to Vieth, the authors accepted his explanation as the probable cause for their findings and also proposed that tissue calcidiol levels, not just tissue calcitriol levels, may be protective. Jacobs ET, Giuliano AR, Martinez ME, Hollis BW, Reid ME, Marshall JR. Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. J Steroid Biochem Mol Biol. 2004 May;89–90(1–5):533–7. Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E. Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control. 2004 Apr;15(3):255–65. Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, Stattin P, Harvei S, Hakulinen T, Luostarinen T, Dillner J, Lehtinen M, Hakama M. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004 Jan 1;108(1):104–8.
Vitamin D "Important" in Prevention of Deaths
Then, researchers in Norway showed that patients diagnosed with prostate cancer in the summer and fall, when vitamin D levels are the highest, have a significantly better prognosis than patients diagnosed in the winter or spring. The authors concluded that their "study supports the hypothesis that vitamin D may influence cancer specific mortality in a beneficial way. A possible mechanism to explain our results might be a combined action of vitamin D and cancer treatment that amplifies the treatment effect. It confirmed, in addition to traditional cancer treatment, vitamin D would be of particular importance in the primary prevention of deaths from cancer." Robsahm TE, Tretli S, Dahlback A, Moan J. Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control. 2004 Mar;15(2):149–58.
Calcidiol An Active Steroid Hormone
Lu and his group from Finland then demonstrated for the first time that calcidiol is an active steroid hormone in prostate cells. Up until this time, most scientists believed calcidiol was only a prehormone and had to be metabolized into calcitriol before it could regulate genes. Although much less potent than calcitriol, calcidiol is present in much higher concentrations. It now appeared calcidiol is a steroid hormone as well as calcitriol and is active in suppressing cell proliferation in prostate tissue. Lou YR, Laaksi I, Syvala H, Blauer M, Tammela TL, Ylikomi T, Tuohimaa P. 25-hydroxyvitamin D3 is an active hormone in human primary prostatic stromal cells. FASEB J. 2004 Feb;18(2):332–4.
Cancer Chemoprevention With Vitamin D
Young and his group at Boston University School of Medicine then confirmed that tissue calcitriol concentrations are virtually uncontrolled. That is, the usual mechanisms that regulate blood calcitriol concentrations, calcium, and parathormone do not regulate tissue calcitriol levels in prostate cells. In fact, calcitriol did not exhibit negative feedback, and reduce its own production, until pharmacological amounts of calcitriol were introduced. The authors also pointed out that soy would further increase tissue levels and concluded their finding should "encourage the further development of nutritionally-based models for prostate cancer chemoprevention using vitamin D." Young MV, Schwartz GG, Wang L, Jamieson DP, Whitlatch LW, Flanagan JN, Lokeshwar BL, Holick MF, Chen TC. The prostate 25-hydroxyvitamin D-1 alpha-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D. Carcinogenesis. 2004 Jun;25(6):967–71.
First Human Interventional Trial
In late 2004, Woo, Vieth, and colleagues from the University of Toronto presented a groundbreaking paper at the November NIH conference on vitamin D and cancer. They showed that 2,000 units of simple vitamin D3 (cholecalciferol) either reduced or prevented further increases in PSA in the majority of men with advancing prostate cancer. For the first time, a human interventional trial indicted that simple vitamin D was effective in fighting cancer.
Still More To Discover
Since then numerous studies have revealed the powerful anti-cancer properties that vitamin D has. Many questions remain unanswered. Many questions are always unanswered, that is the nature of science. But each day brings with it new answers, and vitamin D still has many secrets to reveal.
John Jacob Cannell MD Executive Director 2006.06.04