title: Dietary vitamin D₃ and 1,25-dihydroxyvitamin D₃ (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer.
abstract: 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) 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)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) 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 D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D(3) 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 D(3) comparison was to a maximally safe calcitriol dose. Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D(3) 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 D(3). Both calcitriol and dietary vitamin D(3) 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 D(3) supplementation in cancer prevention and therapy.
authors.affiliation: Department of Medicine-Endocrinology, Stanford University School of Medicine, Stanford, California 94305-5103, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.forename: Aruna V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Wang
authors.forename: Kristin
authors.initials: K
authors.lastname: Jensen
authors.forename: Ronald
authors.initials: R
authors.lastname: Horst
authors.forename: Megan A
authors.initials: MA
authors.lastname: Albertelli
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000008:administration & dosage / Q000494:pharmacology*; D019587:Dietary Supplements; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010052:Ovariectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase; D014815:Vitamins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D018167:Receptors, Calcitriol; D014815:Vitamins; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium