PKI-587 enhances chemosensitivity of oxaliplatin in hepatocellular carcinoma through suppressing DNA damage repair pathway (NHEJ and HR) and PI3K/AKT/mTOR pathway.

Abstract

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.

• Authors: Yinci Zhang, Chunmei Xie, Amin Li, Xueke Liu, Yingru Xing, Jing Shen, Zhen Huo, Shuping Zhou, Xinkuang Liu, Yinghai Xie, Weiya Cao, Yongfang Ma, Ruyue Xu, Shiyu Cai, Xiaolong Tang, Dong Ma
• Journal: American journal of translational research (Am J Transl Res) Vol. 11 Issue 8 Pg. 5134-5149 ( 2019) ISSN: 1943-8141 [Print] United States
• PMID: 31497229 (Publication Type: Journal Article)