Research Group in Molecular Oncology and Endocrinology, Department of Medical Biology, Canada Research Chair in Molecular Gyneco-Oncology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada G9A 5H7.
Endocrinology. 2013 Jul;154(7):2281-95. doi: 10.1210/en.2013-1083. Epub 2013 May 15.
As we previously showed, we have synthesized a new family of 17β-estradiol-platinum(II) hybrids. Earlier studies revealed the VP-128 hybrid to show high efficiency compared with cisplatin toward hormone-dependent breast cancer cells. In the present research, we have studied the antitumor activity of VP-128 in vitro and in vivo against ovarian cancer. In nude mice with ovarian xenografts, VP-128 displayed selective activity toward hormone-dependent tumors and showed higher efficiency than cisplatin to inhibit tumor growth. Similarly, in vitro, transient transfection of estrogen receptor (ER)-α in ERα-negative A2780 cells increased their sensitivity to VP-128-induced apoptosis, confirming the selectivity of VP-128 toward hormone-dependent tumor cells. In agreement, Western blot analysis revealed that VP-128 induced higher caspase-9, caspase-3, and poly (ADP-ribose) polymerase cleavage compared with cisplatin. The activation of caspase-independent apoptosis was also observed in ERα-negative A2780 cells, in which VP-128 rapidly induced the translocation of apoptosis-inducing factor to the nucleus. Conversely, subcellular localization of apoptosis-inducing factor was not modified in ERα-positive Ovcar-3 cells. We also discovered that VP-128 induces autophagy in ovarian cancer cells because of the formation of acidic vesicular organelles (AVOs) and increase of Light Chain 3B-II protein responsible for the formation of autophagosomes; pathways related to autophagy (AKT and mammalian target of rapamycin) were also down-regulated, supporting this mechanism. Finally, the inhibition of autophagy using chloroquine increased VP-128 efficiency, indicating a possible combination therapy. Altogether these results highlight the beneficial value of VP-128 for the treatment of hormone-dependent ovarian cancers and provide preliminary proof of concept for the efficient targeting of ERα- by 17β-estradiol-Pt(II)-linked chemotherapeutic hybrids in these tumors.
正如我们之前所展示的，我们已经合成了一系列新的 17β-雌二醇-铂(II)杂化物。早期的研究表明，VP-128 杂化物在针对激素依赖性乳腺癌细胞方面比顺铂具有更高的效率。在本研究中，我们研究了 VP-128 在体外和体内对卵巢癌的抗肿瘤活性。在荷卵巢异种移植的裸鼠中，VP-128 对激素依赖性肿瘤具有选择性活性，并且比顺铂更有效地抑制肿瘤生长。同样，在体外，瞬时转染雌激素受体 (ER)-α 于 ERα-阴性 A2780 细胞中增加了它们对 VP-128 诱导的细胞凋亡的敏感性，证实了 VP-128 对激素依赖性肿瘤细胞的选择性。Western blot 分析结果一致表明，VP-128 诱导的 caspase-9、caspase-3 和多聚 (ADP-核糖) 聚合酶裂解比顺铂更高。在 ERα-阴性 A2780 细胞中也观察到 caspase 非依赖性凋亡的激活，其中 VP-128 迅速诱导凋亡诱导因子向细胞核易位。相反，在 ERα-阳性 Ovcar-3 细胞中，凋亡诱导因子的亚细胞定位没有改变。我们还发现 VP-128 诱导卵巢癌细胞自噬，因为形成酸性囊泡细胞器 (AVOs) 并增加负责形成自噬体的 Light Chain 3B-II 蛋白；自噬相关途径（AKT 和哺乳动物雷帕霉素靶蛋白）也被下调，支持这种机制。最后，使用氯喹抑制自噬增加了 VP-128 的效率，表明可能的联合治疗。总之，这些结果突出了 VP-128 在治疗激素依赖性卵巢癌方面的有益价值，并为雌激素-铂(II)连接化疗杂化物在这些肿瘤中有效靶向 ERα 提供了初步的概念验证。
