BEZ235 increases sorafenib inhibition of hepatocellular carcinoma cells by suppressing the PI3K/AKT/mTOR pathway

Amin Li; Rongbo Zhang; Yinci Zhang; Xueke Liu; Ruikai Wang; Jiachang Liu; Xinkuang Liu; Yinghai Xie; Weiya Cao; Ruyue Xu; Yongfang Ma; Wenpeng Cai; Binquan Wu; Shuyu Cai; Xiaolong Tang

BEZ235 increases sorafenib inhibition of hepatocellular carcinoma cells by suppressing the PI3K/AKT/mTOR pathway

Am J Transl Res. 2019 Sep 15;11(9):5573-5585. eCollection 2019.

Authors

Amin Li¹, Rongbo Zhang¹, Yinci Zhang¹, Xueke Liu¹, Ruikai Wang², Jiachang Liu², Xinkuang Liu², Yinghai Xie², Weiya Cao¹, Ruyue Xu¹, Yongfang Ma¹, Wenpeng Cai¹, Binquan Wu³, Shuyu Cai¹, Xiaolong Tang¹

Affiliations

¹ Medical School, Anhui University of Science & Technology Huainan 232001, China.
² First Affiliated Hospital, Anhui University of Science & Technology Huainan 232001, China.
³ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China.

PMID: 31632530
PMCID: PMC6789287

Abstract

Background: Sorafenib is an oral multi-kinase inhibitor that inhibits hepatocellular carcinoma (HCC) via the Ras/Raf/MAPK pathway. However, sorafenib loses effectiveness because most tumors acquire drug resistance over time. As the PI3K/AKT/mTOR signaling pathway is also activated abnormally in HCC, we evaluated the effect of sorafenib, in combination with a dual PI3K/mTOR inhibitor, BEZ235, on HCC cell proliferation and survival in vitro.

Materials and methods: Biological phenotypes were analysed in HCC cell lines, parental and sorafenib-resistant HepG2 cells (HepG2 and HepG2^R), treated with sorafenib or BEZ235, alone or in combination. HCC cellular proliferation and apoptosis were investigated, and perturbations of the Ras/Raf/MAPK and PI3K/AKT/mTOR signaling/survival pathways were evaluated by western blot analysis.

Results: BEZ235 enhanced sorafenib inhibition of cellular proliferation, migration, and promotion of apoptosis in HepG2 and HepG2^R cells. The combined effects were associated with inhibition of phosphorylation of AKT, mTOR and S6K in the PI3K/AKT/mTOR pathway, whereas the combination of sorafenib and BEZ235 did not significantly alter the Ras/Raf/MAPK pathway compared with the effect of sorafenib alone.

Conclusion: Sorafenib/BEZ235 combination has potent anti-HCC cell activity. This anti-tumor activity is most likely multi-factorial, mainly involving PI3K down-regulation and AKT, mTOR and S6K dephosphorylation. Combined inhibition of PI3K/AKT/mTOR and Ras/Raf/MAPK pathways enhances sorafenib inhibition of HCC. The results of these in vitro studies suggest that trials of combined sorafenib and BEZ235 in the treatment of HCC should be considered.

Keywords: BEZ235; HepG2 cells; PI3K/AKT/mTOR pathway; Sorafenib; hepatocellular carcinoma.