Department of Pathology, CHA Bundang Medical Center, CHA University, Republic of Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Republic of Korea.
Department of Pathology, CHA Bundang Medical Center, CHA University, Republic of Korea.
Gynecol Oncol. 2019 Apr;153(1):135-148. doi: 10.1016/j.ygyno.2019.01.012. Epub 2019 Jan 25.
Ovarian cancer is the leading cause of gynecologic-related mortality worldwide. Despite successful initial treatment, overall survival rates are very low because tumors develop resistance to chemotherapeutic drugs. The PI3K/mTOR pathway is a key signaling pathway involved in drug resistance of ovarian cancer cells. The aim of this study was to examine the effect of a newly developed PI3K/mTOR dual inhibitor, CMG002, on chemoresistant ovarian cancer cells.
We examined the effects of CMG002, and its synergistic effects when combined with paclitaxel or cisplatin, on cell viability, cell cycle arrest, and apoptosis of PTX-resistant SKpac17 or cisplatin-resistant A2780cis ovarian cancer cells in vitro. Western blot analysis was performed to assess expression of PI3K, p-mTOR, p-Akt, p-S6, Bim, and caspase-3. In vivo studies were carried out in a xenograft mouse model, followed by TUNEL and immunohistochemical staining of excised tumor tissue.
CMG002 showed marked toxicity against chemoresistant ovarian cancer cells and re-sensitized these cells to chemotherapeutic agents by suppressing cell proliferation and inducing G1 cell cycle arrest and apoptosis. In vivo xenograft studies revealed that treatment with CMG002, either alone or in combination with paclitaxel or cisplatin, led to a marked reduction in tumor growth. CMG002 caused marked suppression of mTOR (Ser2448), Akt (Ser473), Akt (Thr308), and S6 (Ser235/236) phosphorylation, both in vitro and in vivo.
Taken together, CMG002, a very potent PI3K/mTOR dual inhibitor, induced cytotoxicity in chemoresistant ovarian cancer cells, suggesting that this novel inhibitor might be a new therapeutic strategy for chemoresistant ovarian cancer.
卵巢癌是全球导致妇科相关死亡的主要原因。尽管初始治疗成功，但总体存活率非常低，因为肿瘤对化疗药物产生耐药性。PI3K/mTOR 通路是参与卵巢癌细胞耐药的关键信号通路。本研究旨在研究新开发的 PI3K/mTOR 双重抑制剂 CMG002 对耐药性卵巢癌细胞的影响。
我们研究了 CMG002 对体外 PTX 耐药 SKpac17 或顺铂耐药 A2780cis 卵巢癌细胞活力、细胞周期停滞和凋亡的影响，及其与紫杉醇或顺铂联合使用的协同作用。通过 Western blot 分析评估 PI3K、p-mTOR、p-Akt、p-S6、Bim 和 caspase-3 的表达。在异种移植小鼠模型中进行体内研究，然后对切除的肿瘤组织进行 TUNEL 和免疫组织化学染色。
CMG002 对耐药性卵巢癌细胞表现出显著的毒性，并通过抑制细胞增殖和诱导 G1 细胞周期停滞和凋亡使这些细胞重新对化疗药物敏感。体内异种移植研究表明，CMG002 单独或与紫杉醇或顺铂联合治疗导致肿瘤生长明显减少。CMG002 导致 mTOR（Ser2448）、Akt（Ser473）、Akt（Thr308）和 S6（Ser235/236）的磷酸化在体外和体内均受到明显抑制。
综上所述，PI3K/mTOR 双重抑制剂 CMG002 在耐药性卵巢癌细胞中诱导细胞毒性，表明这种新型抑制剂可能是治疗耐药性卵巢癌的新策略。
