Dietary Vitamin D3 and 1,25-Dihydroxyvitamin D3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer

Endocrinology - Tập 153 Số 6 - Trang 2576-2587 - 2012
Srilatha Swami1, Aruna V. Krishnan2, Jennifer Y. Wang2, Kristin C. Jensen3,4, Ronald L. Horst5, Megan A. Albertelli6, David Feldman2
1Department of Medicine-Endocrinology, Stanford University School of Medicine, Stanford, California 94305-5103, USA.
2Departments of Medicine-Endocrinology (S.S., A.V.K., J.Y.W., D.F.), Stanford, California 94305
3Department of Pathology and Palo Alto Veterans Affairs Hospital Care Systems (K.J.), Palo Alto, California 94304
4Pathology (K.J.), Stanford, California 94305
5Heartland Assays LLC (R.H.), Ames, Iowa 50010
6Comparative Medicine (M.A.A.), Stanford University School of Medicine, Stanford, California 94305

Tóm tắt

1,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)2D3 formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D3 will be converted to 25(OH)D3 in the body and then to 1,25(OH)2D3 locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D3-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D3 inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 μg and 0.1 μg caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D3 comparison was to a maximally safe calcitriol dose. Dietary vitamin D3 did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D3 diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D3. Both calcitriol and dietary vitamin D3 were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D3 supplementation in cancer prevention and therapy.

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Tài liệu tham khảo

Christakos, 2011, Minireview: vitamin D: is there a role in extraskeletal health?, Endocrinology, 152, 2930, 10.1210/en.2011-0243

Krishnan, 2010, The role of vitamin D in cancer prevention and treatment., Endocrinol Metab Clin North Am, 39, 401, 10.1016/j.ecl.2010.02.011

Garland, 2006, The role of vitamin D in cancer prevention., Am J Public Health, 96, 252, 10.2105/AJPH.2004.045260

Garland, 2007, Vitamin D and prevention of breast cancer: pooled analysis., J Steroid Biochem Mol Biol, 103, 708, 10.1016/j.jsbmb.2006.12.007

Giovannucci, 2005, The epidemiology of vitamin D and cancer incidence and mortality: a review (United States)., Cancer Causes Control, 16, 83, 10.1007/s10552-004-1661-4

Coyle, 2004, The effect of environment on breast cancer risk., Breast Cancer Res Treat, 84, 273, 10.1023/B:BREA.0000019964.33963.09

Cui, 2006, Vitamin D, calcium, and breast cancer risk: a review., Cancer Epidemiol Biomarkers Prev, 15, 1427, 10.1158/1055-9965.EPI-06-0075

Freedman, 2002, Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study., Occup Environ Med, 59, 257, 10.1136/oem.59.4.257

Knight, 2007, Vitamin D and reduced risk of breast cancer: a population-based case-control study., Cancer Epidemiol Biomarkers Prev, 16, 422, 10.1158/1055-9965.EPI-06-0865

Bertone-Johnson, 2005, Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer., Cancer Epidemiol Biomarkers Prev, 14, 1991, 10.1158/1055-9965.EPI-04-0722

Gandini, 2011, Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma., Int J Cancer, 128, 1414, 10.1002/ijc.25439

Li, 2007, A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer., PLoS Med, 4, e103, 10.1371/journal.pmed.0040103

Freedman, 2008, Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial., Cancer Epidemiol Biomarkers Prev, 17, 889, 10.1158/1055-9965.EPI-07-2594

McCullough, 2009, Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort., Breast Cancer Res, 11, R64, 10.1186/bcr2356

Ahn, 2008, Serum vitamin D concentration and prostate cancer risk: a nested case-control study., J Natl Cancer Inst, 100, 796, 10.1093/jnci/djn152

Feldman, 2007, Vitamin D: biology, action and clinical implications, Osteoporosis, 3rd ed, 317

Deeb, 2007, Vitamin D signalling pathways in cancer: potential for anticancer therapeutics., Nat Rev Cancer, 7, 684, 10.1038/nrc2196

Gombart, 2006, Vitamin D compounds: activity against microbes and cancer., Anticancer Res, 26, 2531

Stewart, 2004, Vitamin D and prostate cancer., Exp Biol Med (Maywood), 229, 277, 10.1177/153537020422900401

Verstuyf, 2010, Vitamin D: a pleiotropic hormone., Kidney Int, 78, 140, 10.1038/ki.2010.17

Cheng, 2004, Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase., Proc Natl Acad Sci USA, 101, 7711, 10.1073/pnas.0402490101

Hewison, 2011, Extrarenal 1a-hydroxylase, Vitamin D, 777, 10.1016/B978-0-12-381978-9.10045-9

Chen, 2003, Vitamin D and prostate cancer prevention and treatment., Trends Endocrinol Metab, 14, 423, 10.1016/j.tem.2003.09.004

Krishnan, 2011, Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D., Annu Rev Pharmacol Toxicol, 51, 311, 10.1146/annurev-pharmtox-010510-100611

Klein, 1997, Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice., Nat Med, 3, 402, 10.1038/nm0497-402

Swami, 2011, Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo., Horm Cancer, 2, 190, 10.1007/s12672-011-0073-7

Hershberger, 1999, 1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo., Cancer Res, 59, 2644

Hershberger, 2001, Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis., Clin Cancer Res, 7, 1043

Koshizuka, 1999, Combined effect of vitamin D3 analogs and paclitaxel on the growth of MCF-7 breast cancer cells in vivo., Breast Cancer Res Treat, 53, 113, 10.1023/A:1006123819675

Krishnan, 2010, Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy., Endocrinology, 151, 32, 10.1210/en.2009-0855

Livak, 2001, Analysis of relative gene expression data using real-time quantitative PCR and the 2[−ΔΔC(T)] Method., Methods, 25, 402, 10.1006/meth.2001.1262

Moreno, 2005, Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells., Cancer Res, 65, 7917, 10.1158/0008-5472.CAN-05-1435

Zhao, 1999, Induction of androgen receptor by 1α,25-dihydroxyvitamin D3 and 9-cis retinoic acid in LNCaP human prostate cancer cells., Endocrinology, 140, 1205, 10.1210/endo.140.3.6561

Bradford, 1976, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding., Anal Biochem, 72, 248, 10.1016/0003-2697(76)90527-3

Hollis, 1993, Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer., Clin Chem, 39, 529, 10.1093/clinchem/39.3.529

Hollis, 1996, Quantification of circulating 1,25-dihydroxyvitamin D by radioimmunoassay with 125I-labeled tracer., Clin Chem, 42, 586, 10.1093/clinchem/42.4.586

Allred, 2009, NCCN Task Force Report: estrogen receptor and progesterone receptor testing in breast cancer by immunohistochemistry., J Natl Compr Canc Netw, 7, S1, 10.6004/jnccn.2009.0079

Allred, 1998, Prognostic and predictive factors in breast cancer by immunohistochemical analysis., Mod Pathol, 11, 155

Muindi, 2004, Pharmacokinetics of 1α,25-dihydroxyvitamin D3 in normal mice after systemic exposure to effective and safe antitumor doses., Oncology, 66, 62, 10.1159/000076336

Costa, 1986, Homologous up-regulation of the 1,25 (OH)2 vitamin D3 receptor in rats., Biochem Biophys Res Commun, 137, 742, 10.1016/0006-291X(86)91141-1

Sandgren, 1990, Serum calcium and vitamin D regulate 1,25-dihydroxyvitamin D3 receptor concentration in rat kidney in vivo., Proc Natl Acad Sci USA, 87, 4312, 10.1073/pnas.87.11.4312

Skowronski, 1995, Actions of vitamin D3, analogs on human prostate cancer cell lines: comparison with 1,25-dihydroxyvitamin D3., Endocrinology, 136, 20, 10.1210/endo.136.1.7530193

Wecksler, 1978, Studies on the mode of action of vitamin D—XIV. Quantitative assessment of the structural requirements for the interaction of 1α, 25-dihydroxyvitamin D3 with its chick intestinal mucosa receptor system., J Steroid Biochem, 9, 929, 10.1016/0022-4731(78)90053-5

Colston, 1992, EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro., Biochem Pharmacol, 44, 2273, 10.1016/0006-2952(92)90669-A

Flanagan, 2003, Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion., J Steroid Biochem Mol Biol, 84, 181, 10.1016/S0960-0760(03)00028-1

VanWeelden, 1998, Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089., Endocrinology, 139, 2102, 10.1210/endo.139.4.5892

Zinser, 2005, 1,24(S)-dihydroxyvitamin D2, an endogenous vitamin D2 metabolite, inhibits growth of breast cancer cells and tumors., Anticancer Res, 25, 235

Bhatia, 2009, EB1089 inhibits the parathyroid hormone-related protein-enhanced bone metastasis and xenograft growth of human prostate cancer cells., Mol Cancer Ther, 8, 1787, 10.1158/1535-7163.MCT-09-0064

Blutt, 2000, A calcitriol analogue, EB1089, inhibits the growth of LNCaP tumors in nude mice., Cancer Res, 60, 779

Schwartz, 1995, 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 and prostate cancer cell proliferation in vivo., Urology, 46, 365, 10.1016/S0090-4295(99)80221-0

Vegesna, 2003, Ability of potent vitamin D3 analogs to inhibit growth of prostate cancer cells in vivo., Anticancer Res, 23, 283

Murillo, 2010, Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer., J Steroid Biochem Mol Biol, 121, 403, 10.1016/j.jsbmb.2010.03.009

Newmark, 2009, Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer., Carcinogenesis, 30, 88, 10.1093/carcin/bgn229

Fleet, 2008, Serum metabolite profiles and target tissue gene expression define the effect of cholecalciferol intake on calcium metabolism in rats and mice., J Nutr, 138, 1114, 10.1093/jn/138.6.1114

Tan, 2005, Immunohistochemical detection of Ki67 in breast cancer correlates with transcriptional regulation of genes related to apoptosis and cell death., Mod Pathol, 18, 374, 10.1038/modpathol.3800254

Coddington, 1993, Determination of Ki67 growth fraction and oestrogen receptors in screen-detected breast cancer using cytological preparations., Cytopathology, 4, 257, 10.1111/j.1365-2303.1993.tb00100.x

Matthews, 2010, Genomic vitamin D signaling in breast cancer: insights from animal models and human cells., J Steroid Biochem Mol Biol, 121, 362, 10.1016/j.jsbmb.2010.03.061

Simpson, 2002, Aromatase—a brief overview., Annu Rev Physiol, 64, 93, 10.1146/annurev.physiol.64.081601.142703

Murayama, 2004, Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching., EMBO J, 23, 1598, 10.1038/sj.emboj.7600157

Kemmis, 2006, Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3., J Nutr, 136, 887, 10.1093/jn/136.4.887

Turunen, 2007, Selective use of multiple vitamin D response elements underlies the 1α,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene., Nucleic Acids Res, 35, 2734, 10.1093/nar/gkm179

Ooi, 2010, Vitamin D deficiency promotes growth of MCF-7 human breast cancer in a rodent model of osteosclerotic bone metastasis., Bone, 47, 795, 10.1016/j.bone.2010.07.012

Peng, 2009, 25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture., Breast Cancer Res Treat, 113, 31, 10.1007/s10549-008-9900-0

Young, 2004, The prostate 25-hydroxyvitamin D-1α-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D., Carcinogenesis, 25, 967, 10.1093/carcin/bgh082

Gross, 1998, Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol)., J Urol, 159, 2035, 10.1016/S0022-5347(01)63236-1

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Endocrinology

Tập 153 Số 6

2576-2587

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