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.

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

“…[5][6][7][8] However, cholecalciferol (VD 3 ) and its homolog in plants, ergocalciferol (VD 2 ), are inactive compounds that require bioactivation to exert their biological actions. In mammals (Figure 1), the inactive cholecalciferol, synthesized from its precursor, 7-dehydrocholesterol through skin exposure to UVB light, is first 25-hydroxylated mainly in the liver by either mitochondrial CYP27A1 or microsomal CYP2R1.…”

Chemoprevention Activity of 25-Hydroxyvitamin D in the MMTV-PyMT Mouse Model of Breast Cancer

“…Vitamin D deficiency is not only widespread in patients with cancer, but correlates with advanced-stage disease independently of age, sex, and body mass index (47). Vitamin D deficiency also enhances human breast cancer cell lines growth and metastasis in xenograft models (48)(49)(50) and increases the incidence of chemically induced mammary lesions in rats (51). However, the immune response is a crucial component of cancer progression, and carcinogen induction is a confounding factor, so we used here the MMTV-PyMT model of spontaneous oncogene-driven à , P < 0.05; ÃÃà , P < 0.001.…”

Polymorphic variants in the vitamin D pathway genes and the risk of ovarian cancer among non-carriers of BRCA1/BRCA2 mutations

“…It has been demonstrated that 1,25(OH) 2 D 3 also inhibits proliferation of adrenocortical and pancreatic cancer cells and suppresses hepatocellular carcinoma development by reducing inflammatory cytokine production in vivo (30)(31)(32). In addition, vitamin D inhibits motility, invasion and metastasis of squamous cell carcinoma and suppresses breast and prostate cancer progression in murine models (33,34). Furthermore, the vitamin D analog EB1089 was found to trigger apoptosis of gastric cancer cells, and in preclinical studies exerted an anti-proliferative effect on human OC xenografts in murine models (35,36).…”