AG-1024 Sensitizes Sorafenib-Resistant Hepatocellular Carcinoma Cells to Sorafenib via Enhancing G1/S Arrest

Abstract

Wei Zhou,1– 3 Weiyang Lou,4 Junru Chen,1– 3 Bisha Ding,4 Binjie Chen,2,3,5 Haiyang Xie,1– 3 Lin Zhou,1– 3 Shusen Zheng,1– 3 Donghai Jiang2,3,5 1Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, People’s Republic of China; 3Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Hangzhou, People’s Republic of China; 4Department of Breast Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 5Key Laboratory of Organ Transplantation, Hangzhou, People’s Republic of ChinaCorrespondence: Shusen Zheng Tel [phone]Fax [phone]Email [email protected] Jiang Tel [phone]Fax [phone]Email [email protected]: The frequency in resistance to sorafenib accounts for the grim prognosis of advanced hepatocellular carcinoma (HCC). In the present study, we explore the anti-cancer efficacy of co-administration of sub-toxic AG-1024 with sorafenib in HCC cells to enhance the sensitivity of these cells to sorafenib.Materials and Methods: Two acquired sorafenib-resistant HCC cells, SNU-sora-5 and SK-sora-5, were established and verified. The MTT assay, colony formation assay, cell morphology detection and flow cytometric analysis were then used to determine the anti-tumor effects of the co-administration of sub-toxic AG-1024 and sorafenib. Finally, the potential molecular mechanism was preliminarily examined.Results: Compared to parental cell lines, the acquired sorafenib-resistant cell lines, SNU-sora-5 and SK-sora-5, were more resistant to sorafenib. Sub-toxic AG-1024 markedly enhanced sorafenib-mediated cell inhibition in acquired sorafenib-resistant HCC strains, with a reversal index (RI) of 4.64 in SNU-sora-5 and 4.58 in SK-sora-5 cell lines. Moreover, co-administration of sub-toxic AG-1024 and sorafenib exerted dramatic cytotoxicity compared with sorafenib alone in the intrinsic sorafenib-resistant HCC-LM3 cells. In contrast to high-dose sorafenib, sub-toxic AG-1024 combined with sorafenib had less impact on apoptosis while significantly enhancing G1/S arrest via activation of the mTOR/p21 signaling pathway. The more, pharmacological inhibition of mTOR activity by inhibitor Palomid 529 significantly antagonized the synergistic anti-cancer effects of AG-1024 and sorafenib in HCC cells.Conclusion: The current findings indicate that sub-toxic AG-1024 may be a promising therapeutic agent in enhancing the sensitivity in HCC cells to sorafenib, bringing hope to HCC patients refractory to sorafenib treatment.Keywords: hepatocellular carcinoma, sorafenib resistance, AG-1024, mTOR, G1/S arrest

Keywords

• hepatocellular carcinoma
• sorafenib resistance
• ag-1024
• mtor
• g1/s arrest