Department of Growth and Reproduction, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.
J Steroid Biochem Mol Biol. 2013 Jul;136:238-46. doi: 10.1016/j.jsbmb.2012.10.008. Epub 2012 Oct 23.
The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has anti-proliferative, pro-apoptotic, 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 (1100IU 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. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
活性维生素 D，1,25-二羟维生素 D3（1,25(OH)2D3）在体外和体内的体细胞癌细胞中具有抗增殖、促凋亡和促分化作用。1,25(OH)2D3 还增强了几种化疗药物的抗肿瘤作用，包括顺铂，这可能具有临床相关性。鉴于维生素 D 最近在睾丸生殖细胞瘤（TGCTs）中显示出的促分化作用，我们假设 1,25(OH)2D3 可以作为治疗这些肿瘤的现有化疗方案的有益辅助手段。在这项研究中，研究了 1,25(OH)2D3（另一种促分化化合物）、维甲酸和顺铂对 TGCT 衍生细胞系的细胞存活效应。1,25(OH)2D3 增强了胚胎癌细胞系（NTera2）中顺铂的作用，可能是通过下调多能性基因和同时上调细胞周期调节剂 p21、p27、p53、p73 和 FOXO1，而在 TCam-2 和 2102Ep 细胞系（分别来自精原细胞瘤和胚胎癌）中未发现显著作用。随后在裸鼠的 Ntera2 异种移植肿瘤模型中测试了胆钙化醇、1,25(OH)2D3 和顺铂的体内抗肿瘤作用。在异种移植肿瘤中，1,25(OH)2D3 和顺铂联合治疗导致 OCT4 下调和 p21 和 p73 同时上调，但与单独使用顺铂相比，并未显著减少肿瘤生长。此外，肿瘤形成后补充胆钙化醇饮食（每天 1100IU）并未增加体内顺铂的敏感性。总之，体外添加 1,25(OH)2D3 增强了顺铂单药治疗的抗肿瘤作用，但在体内睾丸生殖细胞癌模型中并非如此。需要进一步研究以确定较低剂量顺铂与维生素 D 联合应用的潜在有益作用，并确定 1,25(OH)2D3 是否可以增加化疗耐药 TGCTs 对顺铂的敏感性。本文是题为“维生素 D 研讨会”的特刊的一部分。
