Rapamycin enhanced the antitumor efficacy of oxaliplatin in cisplatin-resistant ovarian cancer cells A278ocis both in vitro and in vivo
Rapamycin enhanced the antitumor efficacy of oxaliplatin in cisplatin-resistant ovarian cancer cells A278ocis both in vitro and in vivo
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DOI：
10.1179/1973947815y.0000000021
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发表时间：
2015-12-01
影响因子：
1.8
通讯作者：
Xing, Xinli
中科院分区：
文献类型：
--
作者：
Liu, Jin;Zhang, Ling;Xing, Xinli
目的：本研究旨在探讨哺乳动物雷帕霉素靶点（mTOR）抑制剂雷帕霉素（一种治疗器官移植后排斥反应）与第三代铂类药物奥沙利铂（常用于治疗化疗耐药或进行性卵巢癌的第三代铂类药物）联合使用在顺铂耐药卵巢癌细胞A2780cis中的疗效。方法/材料：测定mTOR及其靶分子p70S6K和4E-BP1的表达。使用蛋白质印迹法分别观察顺铂敏感和耐药细胞 A2780 和 A2780cis。使用体外 MTT 测定以及体内裸鼠模型检查 A2780cis 暴露于奥沙利铂或奥沙利铂加雷帕霉素的增殖。采用流式细胞术和Western blotting检测细胞凋亡和促凋亡蛋白，包括caspase-8和-3以及PARP。结果：我们发现A2780cis细胞对顺铂和奥沙利铂具有部分交叉耐药性。与 A2780 细胞相比，A2780cis 细胞中磷酸化 mTOR (p-mTOR)、p70S6K 和 4E-BP1 的水平显着升高，这可能与顺铂诱导的化疗耐药有关。雷帕霉素在体外和体内均明显增强奥沙利铂对A2780cis生长的抑制作用。雷帕霉素轻微诱导细胞凋亡，但显着增强奥沙利铂诱导A2780cis细胞凋亡的作用，这可能归因于其能够进一步增加奥沙利铂诱导的Cleaved Caspase-8和-3以及PARP的水平。结论：这些结果表明奥沙利铂与雷帕霉素联合使用增强了奥沙利铂在A2780cis细胞中的抗肿瘤功效，因此可能在A2780cis细胞中发挥作用。治疗顺铂耐药的卵巢癌。
Objective: This study aimed to investigate the efficacy of combination of rapamycin, an mammalian target of rapamycin (mTOR) inhibitor for treating rejection after organ transplantation, and oxaliplatin, a third-generation of platinum drug usually used to treat chemoresistant or progressive ovarian cancer, in cisplatin-resistant ovarian carcinoma cells A2780cis.Methods/Materials: Expressions of mTOR and its target molecules p70S6K and 4E-BP1 were determined in cisplatin-sensitive and -resistant cells A2780 and A2780cis, respectively, using Western blotting. Proliferation of A2780cis exposure to oxaliplatin or oxaliplatin plus rapamycin was examined using MTT assay in vitro as well as a nude mice model in vivo. Cell apoptosis and proapoptosis proteins including caspase-8 and -3 and PARP were determined using flow cytometry and Western blotting.Results: We found that A2780cis cells had partial cross-resistance between cisplatin and oxaliplatin. The levels of phosphorylated mTOR (p-mTOR), p70S6K, and 4E-BP1 were significantly increased in A2780cis cells compared to A2780 cells, which might be implicated in cisplatin-induced chemoresistance. Rapamycin obviously enhanced the inhibitory effect of oxaliplatin on the growth of A2780cis both in vitro and in vivo. Rapamycin slightly induced cell apoptosis but significantly enhanced the effect of oxaliplatin in soliciting apoptosis of A2780cis cells, which might be ascribed to its ability in further increasing the levels of cleaved caspase-8 and -3 and PARP induced by oxaliplatin.Conclusion: These results suggested that combination of oxaliplatin and rapamycin enhanced the antitumour efficacy of oxaliplatin in A2780cis cells and therefore might have a role in treating cisplatin-resistant ovarian carcinoma.