Zhang Yinci, Xie Chunmei, Li Amin, Liu Xueke, Xing Yingru, Shen Jing, Huo Zhen, Zhou Shuping, Liu Xinkuang, Xie Yinghai, Cao Weiya, Ma Yongfang, Xu Ruyue, Cai Shiyu, Tang Xiaolong, Ma Dong
Medcial School, Anhui University of Science & Technology Huainan 232001, China.
Department of Blood Transfusion, Guangzhou 8th People's Hospital, Guangzhou Medical University Guangzhou 510100, China.
Am J Transl Res. 2019 Aug 15;11(8):5134-5149. eCollection 2019.
Oxaliplatin resistance limits its effectiveness in the treatment of hepatocellular carcinoma (HCC). Abnormal activation of the PI3K/AKT/mTOR pathway has been associated with decreased survival of HCC patients, anti-apoptosis after chemotherapeutic drug-induced DNA damage, and chemoresistance. In this research, we evaluated the effect of the dual PI3K/mTOR inhibitor, PKI-587, on the sensitivity of oxaliplatin in HCC. Two HCC cell lines (HepG2 and SK-Hep1) were used to analyze PKI-587 for DNA damage response, cell proliferation, clonogenic survival, cell cycle and apoptosis after oxaliplatin treatment. A HepG2 tumor-bearing model was used to assess the in vivo effects of the combination of the two compounds. In HCC cells, oxaliplatin stably activated the PI3K/AKT/mTOR pathway, including up-regulation of p-Akt (Ser473), p-mTOR (Ser2448), p-mTOR (Ser2481), p-elF4EBP1, and p-S6K1, and activated the DNA damage repair pathways (non-homologous end joining (NHEJ) and homologous recombination (HR)), up-regulation of p-DNAPKcs (Ser2056), p-ATM (Ser1981), and p-ATR (Ser428), which were attenuated by PKI-587. Compared with oxaliplatin alone, the combination of PKI-587 and oxaliplatin increased the number of γ-H2AX/cells, decreased proliferation of cells, and an increased the percentage of G0/G1 phase cells and apoptotic cells. In vivo, the combination of oxaliplatin with PKI-587 inhibited tumor growth. Anti-tumor effects were associated with induction of mitochondrial apoptosis and inhibition of phosphorylation of mTOR, Akt and γ-H2AX. We conclude that PKI-587 enhances chemosensitivity of oxaliplatin in HCC through suppressing the PI3K/AKT/mTOR signalling pathway and inhibiting the DNA damage repair pathway. The combination of PKI-587 and oxaliplatin appears to be a promising regimen for the treatment of HCC.
奥沙利铂耐药限制了其在肝细胞癌（HCC）治疗中的有效性。PI3K/AKT/mTOR通路的异常激活与HCC患者生存率降低、化疗药物诱导的DNA损伤后的抗凋亡作用以及化疗耐药相关。在本研究中，我们评估了双PI3K/mTOR抑制剂PKI-587对HCC中奥沙利铂敏感性的影响。使用两种HCC细胞系（HepG2和SK-Hep1）分析PKI-587在奥沙利铂处理后的DNA损伤反应、细胞增殖、克隆形成存活、细胞周期和凋亡情况。使用HepG2荷瘤模型评估两种化合物联合使用的体内效果。在HCC细胞中，奥沙利铂稳定激活PI3K/AKT/mTOR通路，包括p-Akt（Ser473）、p-mTOR（Ser2448）、p-mTOR（Ser2481）、p-elF4EBP1和p-S6K1的上调，并激活DNA损伤修复通路（非同源末端连接（NHEJ）和同源重组（HR）），p-DNAPKcs（Ser2056）、p-ATM（Ser1981）和p-ATR（Ser428）上调，而这些均被PKI-587减弱。与单独使用奥沙利铂相比，PKI-587与奥沙利铂联合使用增加了γ-H2AX/细胞数量，减少了细胞增殖，并增加了G0/G1期细胞和凋亡细胞的百分比。在体内，奥沙利铂与PKI-587联合使用抑制肿瘤生长。抗肿瘤作用与线粒体凋亡的诱导以及mTOR、Akt和γ-H2AX磷酸化的抑制相关。我们得出结论，PKI-587通过抑制PI3K/AKT/mTOR信号通路和抑制DNA损伤修复通路增强了奥沙利铂在HCC中的化疗敏感性。PKI-587与奥沙利铂联合使用似乎是一种有前景的HCC治疗方案。
