The active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) has anti-proliferative, pro-apoptotic, and pro-differentiating effects in somatic cancer cells in vitro and in vivo. 1,25(OH)(2)D(3) also augments the anti-tumor effects of several chemotherapeutic agents, including cisplatin, which may have clinical relevance. Given the pro-differentiation effect of vitamin D recently demonstrated in testicular germ cell tumors (TGCTs), we hypothesized that 1,25(OH)(2)D(3) could be a beneficial adjunctive to existing chemotherapy regime used to treat these tumors. In this study, cell survival effects of 1,25(OH)(2)D(3), another pro-differentiation compound, retinoic acid and cisplatin were investigated in TGCT-derived cell lines in vitro. 1,25(OH)(2)D(3) augmented the effect of cisplatin in an embryonal carcinoma-derived cell line (NTera2), possibly through downregulation of pluripotency genes and simultaneous upregulation of the cell cycle regulators p21, p27, p53, p73 and FOXO1, while no significant effects were found in TCam-2 and 2102Ep cell lines (derived from seminoma and embryonal carcinoma, respectively). Anti-tumor effects of cholecalciferol, 1,25(OH)(2)D(3), and cisplatin were subsequently tested in vivo, in a NTera2 xenograft tumor model in nude mice. In xenograft tumors, co-treatment with 1,25(OH)(2)D(3) and cisplatin resulted in downregulation of OCT4 and simultaneous upregulation of p21 and p73, but did not reduce tumor growth significantly more than cisplatin alone. Also, cholecalciferol supplemented diet (1100IU daily) after tumor formation did not increase cisplatin sensitivity in vivo. In conclusion, addition of 1,25(OH)(2)D(3) augmented the antitumor effect of cisplatin monotherapy in vitro, but not in this in vivo testicular germ cell cancer model. Future studies are needed to investigate potential beneficial effects of vitamin D with lower cisplatin doses, and to determine whether 1,25(OH)(2)D(3) may increase cisplatin sensitivity in chemotherapy-resistant TGCTs. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Journal of Steroid Biochemistry and Molecular Biology, 2013, Vol 136, p. 238-246