Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models
Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models
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DOI：
10.1210/en.2005-1450
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发表时间：
2006-04-01
期刊：
影响因子：
4.8
通讯作者：
Kurachi, H
中科院分区：
文献类型：
--
作者：
Ohta, T;Ohmichi, M;Kurachi, H
磷脂酰肌醇3-激酶(PI3K)/Akt级联在卵巢癌细胞体外顺铂耐药中起重要作用；然而，目前还没有关于阻断PI3K/Akt级联是否能增强体内顺铂敏感性的报道。我们在体内卵巢癌模型中研究了抑制PI3K是否会增加顺铂的疗效。用PI3K抑制剂（wortmannin）阻断PI3K/Akt级联，增加了顺铂诱导的抑制Caov-3人卵巢癌细胞株接种的胸腺裸小鼠腹腔内传播和腹水产生的效果。此外，wortmannin增加顺铂诱导的肿瘤细胞凋亡的疗效。在用wortmannin治疗的小鼠中没有检测到副作用。此外，与稳定转染显性阴性Akt （K179M-Akt）的Caov-3细胞相比，用空载体转染的Caov-3细胞接种小鼠的顺铂抗肿瘤作用明显减弱。我们通过免疫组化染色和Western blotting证实了wortmannin在体内阻断Akt磷酸化和PI3K/Akt级联的下游靶点，如BAD （bcl -2相关死亡蛋白）和核因子κ B。与先前报道的体外结果一致，这些体内结果支持顺铂与PI3K抑制剂联合治疗可提高顺铂治疗效果的观点。
The phosphatidylinositol 3-kinase (PI3K)/Akt cascade has an important role in the resistance of ovarian cancer cells to cisplatin in vitro; however, there have been no reports about whether blocking the PI3K/Akt cascade enhances the sensitivity to cisplatin in vivo. We investigated whether inhibition of PI3K increased the efficacy of cisplatin in an in vivo ovarian cancer model. Blocking the PI3K/Akt cascade with a PI3K inhibitor (wortmannin) increased the efficacy of cisplatininduced inhibition of intraabdominal dissemination and production of ascites in athymic nude mice inoculated ip with the Caov-3 human ovarian cancer cell line. In addition, wortmannin increased the efficacy of cisplatin-induced apoptosis in tumors cells. There were no detectable side effects in mice treated with wortmannin. Moreover, the antitumor effect of cisplatin detected in mice inoculated with Caov-3 cells stably transfected with empty vector was significantly attenuated, compared with mice inoculated with Caov-3 cells stably transfected with a dominant- negative Akt, K179M-Akt. We confirmed that wortmannin blocked Akt phosphorylation and the downstream targets of the PI3K/Akt cascade, such as BAD (Bcl-2-associated death protein) and nuclear factor-kappa B in vivo by immunohistochemical staining and Western blotting. In accordance with the previously reported in vitro results, these in vivo results support the idea that combination therapy with cisplatin and a PI3K inhibitor would increase the therapeutic efficacy of cisplatin.