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 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.