TY - JOUR
T1 - Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model
AU - Jørgensen, Anne
AU - Blomberg Jensen, Martin
AU - Nielsen, John Erik
AU - Juul, Anders
AU - Rajpert-De Meyts, Ewa
N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.
PY - 2013
Y1 - 2013
N2 - The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has anti-proliferative, proapoptotic, and pro-differentiating effects in somatic cancer cells in vitro and in vivo. 1,25(OH)2D3 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)2D3 could be a beneficial adjunctive to existing chemotherapy regime used to treat these tumors. In this study, cell survival effects of 1,25(OH)2D3, another pro-differentiation compound, retinoic acid and cisplatin were investigated in TGCT-derived cell lines in vitro. 1,25(OH)2D3 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) 2D3, 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)2D3 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 (1100 IU daily) after tumor formation did not increase cisplatin sensitivity in vivo. In conclusion, addition of 1,25(OH) 2D3 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) 2D3 may increase cisplatin sensitivity in chemotherapy-resistant TGCTs.
AB - The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has anti-proliferative, proapoptotic, and pro-differentiating effects in somatic cancer cells in vitro and in vivo. 1,25(OH)2D3 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)2D3 could be a beneficial adjunctive to existing chemotherapy regime used to treat these tumors. In this study, cell survival effects of 1,25(OH)2D3, another pro-differentiation compound, retinoic acid and cisplatin were investigated in TGCT-derived cell lines in vitro. 1,25(OH)2D3 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) 2D3, 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)2D3 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 (1100 IU daily) after tumor formation did not increase cisplatin sensitivity in vivo. In conclusion, addition of 1,25(OH) 2D3 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) 2D3 may increase cisplatin sensitivity in chemotherapy-resistant TGCTs.
U2 - 10.1016/j.jsbmb.2012.10.008
DO - 10.1016/j.jsbmb.2012.10.008
M3 - Journal article
C2 - 23098692
SN - 0960-0760
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
ER -
