Nsc23925 prevents the development of paclitaxel resistance by inhibiting the introduction of P-glycoprotein and enhancing apoptosis.
Nsc23925 prevents the development of paclitaxel resistance by inhibiting the introduction of P-glycoprotein and enhancing apoptosis.
复制标题
DOI：
10.1002/ijc.29574
复制
发表时间：
2015-10-15
影响因子：
6.4
通讯作者：
Duan Z
中科院分区：
文献类型：
--
作者：
Yang X;Shen J;Gao Y;Feng Y;Guan Y;Zhang Z;Mankin H;Hornicek FJ;Duan Z
预防耐药性出现的策略将提高化疗治疗的有效性，延长卵巢癌患者的生存期。本研究的目的是确定NSC 23925在体外培养细胞和体内小鼠异种移植模型中预防卵巢癌中紫杉醇耐药性发展的作用，并进一步阐明这些潜在机制。我们首先建立了一个紫杉醇耐药的卵巢癌细胞系，并证明了NSC 23925可以通过特异性抑制Pgp的过表达来防止紫杉醇耐药的引入。然后在小鼠模型中通过连续紫杉醇治疗结合或不结合NSC 23925给药建立紫杉醇抗性卵巢癌细胞。大多数单独用紫杉醇连续治疗的小鼠最终发展出紫杉醇抗性，Pgp和抗凋亡蛋白过表达，而在连续施用紫杉醇-NSC 23925组合后，小鼠保持对紫杉醇的敏感性，并显示出较低的Pgp和抗凋亡蛋白表达水平。紫杉醇-NSC 23925处理的小鼠经历了比紫杉醇处理的小鼠显著更长的总体存活时间。此外，紫杉醇和NSC 23925治疗的组合没有诱导明显的毒性，如通过小鼠体重变化、血细胞计数和内脏组织学所测量的。总的来说，我们的观察提供了证据表明，NSC 23925与紫杉醇联合治疗可以预防Pgp或抗凋亡介导的紫杉醇耐药的发生，并改善卵巢癌患者的长期临床结局。
Strategies to prevent the emergence of drug resistance will increase the effectiveness of chemotherapy treatment and prolong survival of women with ovarian cancer. The aim of the current study is to determine the effects of NSC23925 on preventing the development of paclitaxel resistance in ovarian cancer both in cultured cells in vitro and in mouse xenograft models in vivo, and to further elucidate these underlying mechanisms. We first developed a paclitaxel-resistant ovarian cancer cell line, and demonstrated that NSC23925 could prevent the introduction of paclitaxel resistance by specifically inhibiting the overexpression of Pgp in vitro. The paclitaxel-resistant ovarian cancer cells were then established in a mouse model by continuous paclitaxel treatment in combination with or without NSC23925 administration in the mice. The majority of mice continuously treated with paclitaxel alone eventually developed paclitaxel resistance with overexpression of Pgp and anti-apoptotic proteins, whereas mice remained sensitivity to paclitaxel and displayed lower expression levels of Pgp and anti-apoptotic proteins after administered continuously with combination paclitaxel-NSC23925. Paclitaxel-NSC23925 treated mice experienced significantly longer overall survival time than paclitaxel-treated mice. Furthermore, the combination of paclitaxel and NSC23925 therapy did not induce obvious toxicity as measured by mice body weight changes, blood cell counts, and histology of internal organs. Collectively, our observations provide evidence that NSC23925 in combination with paclitaxel may prevent the onset of Pgp or anti-apoptotic-mediated paclitaxel resistance, and improve the long-term clinical outcome in patients with ovarian cancer.