DNC News: Vitamin D and Cancer
Subject: Sunlight and vitamin D prevent cancer. Supplementation may inhibit cancer cell growth.
There is a clear and long studied protective relationship between sunlight exposure and the development of cancer; this relationship was first published in 1941. [i] The more sun exposure the lower the risk for most cancers. Early studies noted the difference in cancer mortality was related to the geographical latitude of a person's home. The further from the equator, the higher the cancer risk. The further north (or I suppose south in the southern hemisphere) one lives, the less direct sunlight exposure, the less ultraviolet light and therefore the lower the amount of vitamin D. Current knowledge says that ultraviolet light exposure is protective against a long list of cancers [ii] including, breast, [iii] [iv] colon, [v] ovary, and prostate, [vi] [vii] [viii] non-Hodgkin's lymphoma, [ix] bladder, endometrial, renal cancer, and multiple myeloma.
More recent studies link low vitamin D levels with increased risk of cancer. A 2000 Finnish study linked low vitamin D levels to greater risk of prostate occurrence and to the development of more aggressive forms. [x] Vitamin D and calcium together lower colon cancer [xi] and breast cancer risk. [xii] [xiii]
It is estimated that 22,000 cancer deaths a year in the United States result from low sun exposure and resulting low Vitamin D levels. [xiv]
Even newer studies look at how vitamin D interacts directly with various types of cancer cells. Vitamin D inhibits the growth of specific types of cancer cells including pancreatic cancer, [xv] ovarian cancer, [xvi] prostate cancer, [xvii] [xviii] colon cancer, [xix]
[i] Apperly FL.
The relation of solar radiation to cancer mortality in North America . Cancer Res. 1941;1:191-195
[ii] Recent Results Cancer Res. 2003;164:371-7.
Ecologic studies of solar UV-B radiation and cancer mortality rates.
Solar ultraviolet B (UV-B) radiation (280-320 nm) has been associated with reduced risk of cancer of the breast, colon, ovary, and prostate, as well as non-Hodgkin's lymphoma (NHL) through the production of vitamin D in papers extending back to 1980. Using data on the geographic distribution of cancer mortality rates in the US, another ten cancers have been added to the list for which UV-B/vitamin D is a risk reduction factor (Grant 2002b; submitted). These associations persist even after additional cancer risk and risk reduction factors such as smoking, urban or rural residence, Hispanic heritage, poverty, dietary factors, and use of nonsteroidal anti-inflammatory drugs are added to the analysis. As a further test of the protective role of UV-B radiation, an ecologic study of cancer mortality rates in Europe with UV-B radiation and dietary factors was conducted. Inverse correlations are found for UV-B radiation for a number of cancers, with those for bladder, breast, endometrial, ovarian, prostate, and renal cancer, and multiple myeloma and NHL having the strongest correlations in this and ongoing multicountry ecologic studies. These studies add further support for the role of UV-B radiation and vitamin D in reducing the risk of a large number of cancers.
PMID: 12899536 [PubMed - indexed for MEDLINE]
[iii] Cancer. 2002 Jan 1;94(1):272-81.
An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates.
Newport News , Virginia , USA . firstname.lastname@example.org
BACKGROUND: The role of diet in the etiology of breast carcinoma has been debated for decades. The ecologic approach generally finds that dietary fat is highly associated with breast carcinoma mortality, with fish intake and solar ultraviolet-B (UV-B) radiation, a source of vitamin D, inversely associated. Case-control and cohort studies generally find a variety of chemical, nonfat dietary, environmental, genetic, lifestyle, and reproductive factors to be important. METHODS: An ecologic study was conducted using breast carcinoma mortality rates (1989-1996), dietary supply data, and latitude (an index of solar UV-B radiation) from 35 countries. RESULTS: The fraction of energy derived from animal products (risk) combined with that from vegetable products (risk reduction), followed by solar UV-B radiation and, to a lesser extent, energy derived from alcohol (risk) and fish intake (risk reduction), were found to explain 80% of the variance of breast carcinoma mortality rates. Dietary fat contributed insignificantly in regressions involving the other factors. CONCLUSIONS: It is hypothesized that animal products are associated with risk for breast carcinoma because they are associated with greater amounts of insulin-like growth factor-1 and lifetime doses of estrogen. Vegetable products contain several risk reduction components including antioxidants and phytoestrogens. The association with latitude is very likely because of solar UV-B radiation and vitamin D. Alcohol modulates estrogen's effects on breasts . Fish intake is associated with risk reduction through vitamin D and n-3 oils . These results are consistent with those of many case-control and cohort studies but should be assessed in well designed cohort studies. Copyright 2002 American Cancer Society.
PMID: 11815987 [PubMed - indexed for MEDLINE]
[iv] Int J Epidemiol. 1990 Dec;19(4):820-4.
Sunlight and breast cancer incidence in the USSR .
Gorham ED, Garland FC, Garland CF.
Department of Community and Family Medicine, University of California, San Diego, School of Medicine, La Jolla 92093.
Epidemiological and laboratory evidence suggest that vitamin D may play a role in reducing risk of breast cancer. Lack of exposure to ultraviolet sunlight can increase the prevalence of vitamin D deficiency, and may place some populations at higher risk of breast cancer. The association between total average annual sunlight energy striking the ground and age-adjusted breast cancer incidence rates in the USSR was evaluated. Breast cancer had a threefold range of incidence. Sunlight levels varied from 210 to 400 calories per cm2 per day. A statistically significant negative association was found between breast cancer incidence rates and total sunlight levels (R = -0.75, p = 0.001). The slope of the regression line corresponded to two additional cases per 100,000 per year for each reduction of 35 calories per cm2 of sunlight. The pattern of increased breast cancer incidence in regions of low solar radiation in the USSR is consistent with the geographical pattern seen for breast cancer mortality in the US and worldwide. A positive relationship between socioeconomic status and breast cancer incidence was also present in the Soviet Union, based on an approximate socioeconomic measure, the number of doctors per 1000 population (R = +0.89, p = 0.0001). The possibility that correlates of socioeconomic status, such as dietary, ethnic, or behavioural factors, could account for the association is discussed.
PMID: 2084008 [PubMed - indexed for MEDLINE]
[v] Int J Epidemiol. 1980 Sep;9(3):227-31.
Do sunlight and vitamin D reduce the likelihood of colon cancer ?
Garland CF, Garland FC.
It is proposed that vitamin D is a protective factor against colon cancer. This hypothesis arose from inspection of the geographic distribution of colon cancer deaths in the U.S. , which revealed that colon cancer mortality rates were highest in places where populations were exposed to the least amounts of natural light--major cities, and rural areas in high latitudes. The hypothesis is supported by a comparison of colon cancer mortality rates in areas that vary in mean daily solar radiation penetrating the atmosphere. A mechanism involving cholecalciferol (vitamin D3) is suggested. The possibility that an ecological fallacy or other indirect association explains the findings is explored.
PMID: 7440046 [PubMed - indexed for MEDLINE]
[vi] Cancer. 1992 Dec 15;70(12):2861-9.
Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation.
Hanchette CL, Schwartz GG.
Department of Geography, University of North Carolina , Chapel Hill .
BACKGROUND. Prostate cancer is the most prevalent nonskin cancer among men in the United States and is the second leading cause of cancer deaths in men. The cause of prostate cancer remains obscure. Recently it was hypothesized that low levels of vitamin D, a hormone with potent antitumor properties, may increase the risk for clinical prostate cancer. METHODS. Because the major source of vitamin D is casual exposure to ultraviolet (UV) radiation, the authors examined the geographic distributions of UV radiation and prostate cancer mortality in 3073 counties of the contiguous United States using linear regression and trend surface analyses. RESULTS. The geographic distributions of UV radiation and prostate cancer mortality are correlated inversely (P < 0.0001). Prostate cancer mortality exhibits a significant north-south trend, with lower rates in the South. These geographic patterns are not readily explicable by other known risk factors for prostate cancer. CONCLUSIONS. These data lend support to the hypothesis that UV radiation may protect against clinical prostate cancer. Viewed in conjunction with other recent data, including those demonstrating a differentiating effect of vitamin D on human prostate cancer cells, these findings suggest that vitamin D may have an important role in the natural history of prostate cancer.
PMID: 1451068 [PubMed - indexed for MEDLINE]
[vii] Lancet. 2001 Aug 25;358(9282):641-2.
Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer .
Luscombe CJ, Fryer AA, French ME, Liu S, Saxby MF, Jones PW, Strange RC.
A positive association between latitude and prostate cancer mortality has been interpreted to indicate that ultraviolet radiation (UVR) protects against development of this cancer. We aimed to examine this hypothesis. We compared exposure between 210 cases and 155 controls. Childhood sunburn (odds ratio 0.18, 95% CI 0.08-0.38), regular foreign holidays(0.41, 0.25-0.68), sunbathing score (0.83, 0.76-0.89), and low exposure to UVR (3.03, 1.59-5.78) were associated with development of prostate cancer. Furthermore, cases with low UVR exposure developed cancer at a younger median age (67.7 years, IQR 61.5-74.6) than cases with higher exposure (72.1 years, 67.5-76.4); p=0.006. These findings are compatible with UVR having a protective role against prostate cancer.
PMID: 11530156 [PubMed - indexed for MEDLINE]
[viii] Cancer Lett. 2003 Mar 31;192(2):145-9.
Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight.
Bodiwala D, Luscombe CJ, Liu S, Saxby M, French M, Jones PW, Fryer AA, Strange RC.
Department of Urology, North Staffordshire Hospital , Staffordshire, Stoke-on-Trent , UK .
Recent studies have suggested that exposure to ultraviolet (UV) radiation may be protective to some internal cancers including that in the prostate. We describe a confirmatory study in 212 prostatic adenocarcinoma and 135 benign prostatic hypertrophy patients designed to determine whether previous findings showing a protective effect for UV exposure could be reproduced. We used a validated questionnaire to obtain data on aspects of lifetime exposure to UV. The data confirmed that higher levels of cumulative exposure, adult sunbathing, childhood sunburning and regular holidays in hot climates were each independently and significantly associated with a reduced risk of this cancer.
PMID: 12668278 [PubMed - indexed for MEDLINE]
[ix] Cancer Epidemiol Biomarkers Prev. 2004 Jan;13(1):59-64.
Ultraviolet radiation and incidence of non-Hodgkin's lymphoma among Hispanics in the United States .
Hu S, Ma F, Collado-Mesa F, Kirsner RS.
Department of Dermatology and Cutaneous Surgery, Sylvester Cancer Center, University of Miami School of Medicine, Miami, Florida, USA.
Non-Hodgkin's lymphoma (NHL) is one of the most common cancers among American Hispanics. Several studies suggest that solar UV radiation (UVR) may be an environmental risk contributing to the rise of NHL over the past decades. These studies focused primarily on light-skinned Caucasian populations; it is unknown what role UVR plays in NHL for Hispanics. We described the incidence of NHL in Hispanics from selected states in the United States between 1989 and 2000. To evaluate the role of UVR, we correlated cancer rates with the UV index and latitude of residency. Variations in NHL incidence rates with estimated amount of UVR among whites and blacks from the selected states were also analyzed. We found that NHL occurred less frequently in Hispanics than in whites. Hispanic men had higher incidence of NHL than Hispanic women. Incidence rates of NHL in Hispanics were inversely associated with estimated amount of UVR as an increase in NHL was observed with decreasing UV index (r = -0.7 in men; r = -0.41 in women) or increasing latitude of residency (r = 0.59 in men; r = 0.48 in women). This trend, although it did not reach statistical significance, was also observed in whites and blacks. Our findings do not support previous reports of a positive association between solar radiation and NHL. The inverse relationship between UVR and incidence of NHL is unexplained but presents the need for generation of hypotheses regarding the epidemiology of causal factors for NHL in the United States . Additional studies should be conducted to clarify whether sunlight exposure contributes to the development of NHL.
PMID: 14744734 [PubMed - indexed for MEDLINE]
[x] [x] Cancer Causes Control. 2000 Oct;11(9):847-52.
Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels ( Finland ).
Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P.
University of Tampere , Medical School , Finland .
OBJECTIVES: The aim was to evaluate the association between serum vitamin D (25-hydroxyvitamin D) level and risk of prostate cancer. METHODS: The nested case-control study was based on a 13-year follow-up of about 19,000 middle-aged men who attended the first screening visit within the Helsinki Heart Study and were free of clinically verified prostate cancer at baseline. Through record linkage with the files of the Finnish Cancer Registry, 149 prostate cancer cases were identified in the cohort. They were matched (1:4) to probability density sampled controls for age, time of sample retrieval, and residence. Serum levels of 25-hydroxyvitamin D (25-VD) at entry were measured for cases and controls. The relative risks of prostate cancer were derived using conditional logistic regression analysis. RESULTS: Prostate cancer risk, analyzed by quartiles of the 25-VD levels, was inversely related to 25-VD. Men with 25-VD concentration below the median had an adjusted relative risk (OR) of 1.7 compared to men with 25-VD level above the median. The prostate cancer risk was highest among younger men (< 52 years) at entry and low serum 25-VD (OR 3.1 nonadjusted and 3.5 adjusted). Among those younger men (< 52 years), low 25-VD entailed a higher risk of non-localized cancers (OR 6.3). The mean age at diagnosis of the patients with 25-VD concentration above the median was 1.8 years higher than that of patients with vitamin D below the median (63.1 vs 61.3 years). CONCLUSIONS: We conclude that low levels of 25-VD associated with an increased risk for subsequent earlier exposure and more aggressive development of prostate cancer, especially before the andropause.
Vitamin D and calcium appear to reduce risk of breast cancer in women.
PMID: 11075874 [PubMed - indexed for MEDLINE]
[xi] Am J Clin Nutr. 1991 Jul;54(1 Suppl):193S-201S.
Can colon cancer incidence and death rates be reduced with calcium and vitamin D?
Garland CF, Garland FC, Gorham ED.
Department of Community and Family Medicine, University of California , San Diego , La Jolla 92093-0607.
It was proposed in 1980 that vitamin D and calcium could reduce the risk of colon cancer. This assertion was based on the decreasing gradient of mortality rates from north to south, suggesting a mechanism related to a favorable influence of ultraviolet-induced vitamin D metabolites on metabolism of calcium. A 19-y prospective study of 1954 Chicago men found that a dietary intake of greater than 3.75 micrograms vitamin D/d was associated with a 50% reduction in the incidence of colorectal cancer, whereas an intake of greater than or equal to 1200 mg Ca/d was associated with a 75% reduction. Clinical and laboratory studies further support these findings. A nested case-control study based on serum drawn from a cohort of 25,620 individuals reported that moderately elevated concentrations of 25-hydroxyvitamin D, in the range 65-100 nmol/L, were associated with large reductions (P less than 0.05) in the incidence of colorectal cancer.
PMID: 2053561 [PubMed - indexed for MEDLINE]
[xii] J Am Coll Nutr. 1999 Oct;18(5 Suppl):392S-397S.
Link to free full text: http://www.jacn.org/cgi/content/full/18/suppl_5/392S
Vitamin D, calcium and prevention of breast cancer: a review .
Lipkin M, Newmark HL.
Weill Medical College of Cornell University, Strang Cancer Research Laboratory at The Rockefeller University, New York, NY 10021-6007, USA.
Several recent epidemiologic and experimental studies have suggested that decreased calcium and vitamin D intake and high dietary fat are associated with mammary gland carcinogenesis. Complete reduction or elimination of human exposure to environmental factors such as high-fat diets is inherently difficult to implement. Recent studies have begun to evaluate a possible role for increased dietary calcium and vitamin D in reducing the risk of colonic and mammary cancers, even in the presence of a high-fat diet. Studies from our laboratory recently found that decreased dietary calcium and vitamin D in a high-fat diet induced adverse changes in the mammary gland and several other organs, which were reversed by increasing dietary calcium and vitamin D; the findings further suggest a possible role for increased dietary calcium and vitamin D in the chemoprevention of these cancers.
PMID: 10511319 [PubMed - indexed for MEDLINE]
[xiii] J Natl Cancer Inst. 2002 Sep 4;94(17):1301-11.
Intake of dairy products, calcium, and vitamin D and risk of breast cancer.
Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA , Willett WC.
Department of Nutrition, Harvard School of Public Health , Boston , MA 02115 , USA .
BACKGROUND: Laboratory data suggest that calcium and vitamin D, found at high levels in dairy products, might reduce breast carcinogenesis. However, epidemiologic studies regarding dairy products and breast cancer have yielded inconsistent results. We examined data from a large, long-term cohort study to evaluate whether high intake of dairy products, calcium, or vitamin D is associated with reduced risk of breast cancer. METHODS: We followed 88 691 women in the Nurses' Health Study cohort from the date of return of their food-frequency questionnaire in 1980 until May 31, 1996 . Dietary information was collected in 1980 and updated in 1984, 1986, 1990, and 1994. We identified 3482 women (premenopausal = 827, postmenopausal = 2345, and uncertain menopausal status = 310) with incident invasive breast cancer. We used pooled logistic regression to estimate multivariable relative risks (RRs) using 2-year time increments. The RRs and 95% confidence intervals (CIs) were calculated for each category of intake compared with the lowest intake group. All statistical tests were two-sided. RESULTS: Intakes of dairy products, calcium, or vitamin D were not statistically significantly associated with breast cancer risk in postmenopausal women. In premenopausal women, however, consumption of dairy products, especially of low-fat dairy foods and skim/low-fat milk, was inversely associated with risk of breast cancer. The multivariable RRs comparing highest (>1 serving/day) and lowest (<or=3 servings/month) intake categories were 0.68 (95% CI = 0.55 to 0.86) for low-fat dairy foods and 0.72 (95% CI = 0.56 to 0.91) for skim/low-fat milk. Dairy calcium (>800 mg/day versus <or=200 mg/day; RR = 0.69, 95% CI = 0.48 to 0.98), total vitamin D (>500 IU/day versus <or=150 IU/day; RR = 0.72, 95% CI = 0.55 to 0.94), and lactose (quintile 5 versus quintile 1; RR = 0.68, 95% CI = 0.54 to 0.86] also had inverse associations with premenopausal breast cancer risk. By taking into account supplemental calcium and vitamin D intake, we found that association with calcium was due mainly to dairy sources whereas the association with vitamin D may be independent of dairy intake. CONCLUSIONS: We found no association between intake of dairy products and breast cancer in postmenopausal women. Among premenopausal women, high intake of low-fat dairy foods, especially skim/low-fat milk, was associated with reduced risk of breast cancer. Similar inverse associations were seen with components (calcium and vitamin D) of dairy foods, but their independent associations with breast cancer are difficult to distinguish.
PMID: 12208895 [PubMed - indexed for MEDLINE]
[xiv] Cancer. 2002 Mar 15;94(6):1867-75.
An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation.
BACKGROUND: There are large geographic gradients in mortality rates for a number of cancers in the U.S. (e.g., rates are approximately twice as high in the northeast compared with the southwest). Risk factors such as diet fail to explain this variation. Previous studies have demonstrated that the geographic distributions for five types of cancer are related inversely to solar radiation. The purpose of the current study was to determine how many types of cancer are affected by solar radiation and how many premature deaths from cancer occur due to insufficient ultraviolet (UV)-B radiation. METHODS: UV-B data for July 1992 and cancer mortality rates in the U.S. for between 1970-1994 were analyzed in an ecologic study. RESULTS: The findings of the current study confirm previous results that solar UV-B radiation is associated with reduced risk of cancer of the breast, colon, ovary, and prostate as well as non-Hodgkin lymphoma. Eight additional malignancies were found to exhibit an inverse correlation between mortality rates and UV-B radiation: bladder, esophageal, kidney, lung, pancreatic, rectal, stomach, and corpus uteri. The annual number of premature deaths from cancer due to lower UV-B exposures was 21,700 (95% confidence interval [95% CI], 20,400-23,400) for white Americans, 1400 (95% CI, 1100-1600) for black Americans, and 500 (95% CI, 400-600) for Asian Americans and other minorities. CONCLUSIONS: The results of the current study demonstrate that much of the geographic variation in cancer mortality rates in the U.S. can be attributed to variations in solar UV-B radiation exposure. Thus, many lives could be extended through increased careful exposure to solar UV-B radiation and more safely, vitamin D3 supplementation, especially in nonsummer months. Copyright 2002 American Cancer Society.
PMID: 11920550 [PubMed - indexed for MEDLINE]
[xv] Carcinogenesis. 2004 Jun;25(6):1015-26. Epub 2004 Jan 23.
Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3.
Schwartz GG, Eads D, Rao A, Cramer SD, Willingham MC, Chen TC, Jamieson DP, Wang L, Burnstein KL, Holick MF, Koumenis C.
Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem , NC 27157 , USA .
The steroid hormone 1,25-dihydroxyvitamin D(3), [1,25(OH)(2)D(3), calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D(3), the prohormone of 1,25(OH)(2)D(3), is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-alpha-hydroxylase [1 alpha(OH)ase]. 1 alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1 alpha(OH)ase is highly expressed in both normal and malignant pancreatic tissue. Expression of this enzyme and enzymatic activity was also detected in four pancreatic tumor cell lines. 25(OH)D(3) inhibited the growth of three of four pancreatic cell lines in a manner that correlated with the level of induction of the cyclin-dependent kinase inhibitors p21 and p27 and with the induction of cell cycle arrest at the G(1)/S checkpoint. The growth of a cell line stably transfected with a mutant Ki-ras allele and of a second cell line with an endogenous Ki-ras activating mutation was also inhibited by 25(OH)D(3), indicating that activating Ki-Ras mutations, which occur in almost 90% of pancreatic adenocarcinomas, do not interfere with the growth-inhibitory effects of 25(OH)D(3). The expression of 1 alpha(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D(3) may offer possible therapeutic and chemopreventive options for pancreatic cancer.
PMID: 14742320 [PubMed - indexed for MEDLINE]
[xvi] Int J Cancer. 2004 Jan 20;108(3):367-73.
Role of 24-hydroxylase in vitamin D3 growth response of OVCAR-3 ovarian cancer cells.
Miettinen S, Ahonen MH, Lou YR, Manninen T, Tuohimaa P, Syvala H, Ylikomi T.
Department of Cell Biology, Medical School , University of Tampere , Tampere , Finland . email@example.com
Vitamin D and its analogues are potent regulators of cell growth and differentiation both in vivo and in vitro. We studied the effects of 25-hydroxyvitamin D(3) [25(OH)D(3)], 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and vitamin D analogue, EB 1089, on the growth of a human ovarian cancer cell line, OVCAR-3. We also studied the expression of vitamin D metabolising enzymes 24-hydroxylase (24OHase) and 1alpha-hydroxylase (1alphaOHase). Our results showed that high concentrations (10 and 100 nM) of 1,25(OH)(2)D(3) inhibited a cell proliferation, whereas low concentration (0.1 nM) stimulated growth of the OVCAR-3 cells. In the concentration range of 10-500 nM a prohormone, 25(OH)D(3), stimulated growth. An amount of 1 nM EB 1089 and 100 nM 1,25(OH)(2)D(3) inhibited growth with an equal magnitude. The expression of 24OHase was strongly induced by 1,25(OH)(2)D(3) and EB 1089 in OVCAR-3 cells, and analysis of vitamin D metabolites showed the functionality of 24OHase. An inhibition of 24OHase activity with a novel 24OHase inhibitor enhanced growth-inhibiting effects of 1,25(OH)(2)D(3) and suppressed the growth stimulation of 100 nM 25(OH)D(3). We also report the expression of a vitamin D activating enzyme, 1alphaOHase, in 7 ovarian cancer cell lines. The production of 1,25(OH)(2)D(3) in OVCAR-3 cells was low, possibly due to an extensive activity of 24OHase or a low 1alphaOHase activity. These results suggest that in ovarian cancer cells vitamin D metabolizing enzymes might play a key role in modulating the growth response to vitamin D. The possible mitogenic effects of vitamin D should be considered when evaluating treatment of ovarian cancer with vitamin D. Copyright 2003 Wiley-Liss, Inc.
PMID: 14648702 [PubMed - indexed for MEDLINE]
[xvii] FASEB J. 2004 Feb;18(2):332-4. Epub 2003 Dec 04.
25-hydroxyvitamin D3 is an active hormone in human primary prostatic stromal cells.
Lou YR, Laaksi I, Syvala H, Blauer M, Tammela TL, Ylikomi T, Tuohimaa P.
Department of Anatomy, Medical School , FIN 33014, University of Tampere , Finland . firstname.lastname@example.org
According to the present paradigm, 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3] is a biologically active hormone; whereas 25-hydroxyvitamin D3 (25OHD3) is regarded as a prohormone activated through the action of 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase). Although the role of vitamin D3 in the regulation of growth and differentiation of prostatic epithelial cells has been well studied, its action and metabolism in prostatic stroma are still largely unknown. We investigated the effects of 25OHD3 and 1alpha,25-(OH)2D3 on two human stromal primary cultures termed P29SN and P32S. In a cell proliferation assay, 25OHD3 was found at physiological concentrations of 100-250 nM to inhibit the growth of both primary cultures, whereas 1alpha,25-(OH)2D3 at a pharmacological concentration of 10 nM exhibited the growth-inhibitory effects on P29SN cells but not on P32S cells. Quantitative real-time RT-PCR analysis revealed that both 25OHD3 and 1alpha,25-(OH)2D3 induced 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) mRNA in a dose- and time-dependent manner. By inhibiting 1alpha-hydroxylase and/or 24-hydroxylase enzyme activities, the induction of 24-hydroxylase mRNA by 250 nM 25OHD3 was clearly enhanced, suggesting that 1alpha-hydroxylation is not a prerequisite for the hormonal activity of 25OHD3. Altogether our results suggest that 25OHD3 at a high but physiological concentration acts as an active hormone with respect to vitamin D3 responsive gene regulation and suppression of cell proliferation.
PMID: 14657005 [PubMed - indexed for MEDLINE]
[xviii] J Cell Biochem. 2003 Feb 1;88(2):363-71.
Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression.
Krishnan AV, Peehl DM, Feldman D.
Department of Medicine, Stanford University School of Medicine, Stanford , California 94305 , USA .
Prostate cancer (PCa) cells express vitamin D receptors (VDR) and 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits the growth of epithelial cells derived from normal, benign prostate hyperplasia, and PCa as well as established PCa cell lines. The growth inhibitory effects of 1,25(OH)(2)D(3) in cell cultures are modulated tissue by the presence and activities of the enzymes 25-hydroxyvitamin D(3) 24-hydroxylase which initiates the inactivation of 1,25(OH)(2)D(3) and 25-hydroxyvitamin D(3) 1alpha-hydroxylase which catalyses its synthesis. In LNCaP human PCa cells 1,25(OH)(2)D(3) exerts antiproliferative activity predominantly by cell cycle arrest through the induction of IGF binding protein-3 (IGFBP-3) expression which in turn increases the levels of the cell cycle inhibitor p21 leading to growth arrest. cDNA microarray analyses of primary prostatic epithelial and PCa cells reveal that 1,25(OH)(2)D(3) regulates many target genes expanding the possible mechanisms of its anticancer activity and raising new potential therapeutic targets. Some of these target genes are involved in growth regulation, protection from oxidative stress, and cell-cell and cell-matrix interactions. A small clinical trial has shown that 1,25(OH)(2)D(3) can slow the rate of prostate specific antigen (PSA) rise in PCa patients demonstrating proof of concept that 1,25(OH)(2)D(3) exhibits therapeutic activity in men with PCa. Further investigation of the role of calcitriol and its analogs for the therapy or chemoprevention of PCa is currently being pursued. Copyright 2002 Wiley-Liss, Inc.
PMID: 12520538 [PubMed - indexed for MEDLINE]
[xix] Biochem Biophys Res Commun. 2001 Jul 27;285(4):1012-7.
25-hydroxy-vitamin d metabolism in human colon cancer cells during tumor progression.
Bareis P, Bises G, Bischof MG, Cross HS, Peterlik M.
Department of Pathophysiology, University of Vienna Medical School , Vienna , A-1090, Austria .
RT-PCR analysis showed elevated expression of 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase) and of 25-hydroxyvitamin D-24-hydroxylase (24-OHase) in well differentiated human colon carcinomas in comparison to normal mucosa. Further tumor progression is associated with a rise in 1alpha-OHase but with no significant change in 24-OHase mRNA expression. Accordingly, HPLC analysis of 25-hydroxy-vitamin D3 metabolism in freshly isolated tumor cells indicated that well to moderately differentiated colon cancers in situ are able to produce 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) and convert it through 24-OHase activity into side-chain modified metabolites, 1,24,25-(OH)3-D3 and 1,25-(OH)2- 24-oxo-D3. Likewise, 25-(OH)-D3 is metabolized into 24,25-(OH)2D3, 23,25-(OH)2D3, and 23,25-(OH)2-24-oxo-D3. Poorly-differentiated cancers expressed low levels of 1alpha-OHase mRNA, whereas 24-OHase was even over-expressed. RT-PCR and HPLC analysis of vitamin D metabolism in primary culture cell clones strongly suggested that the extent of endogenously produced 1alpha,25-(OH)2-D3 was inversely related to 24-OHase activity, which could thus limit the antimitotic efficacy of 1alpha,25-(OH)2-D3 particularly at late stages of colon cancer progression. Copyright 2001 Academic Press.
PMID: 11467853 [PubMed - indexed for MEDLINE]