Arsenic trioxide potentiates the anti-cancer activities of sorafenib against hepatocellular carcinoma by inhibiting Akt activation
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Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but it also induces the activation of Akt, which contributes to the mechanisms for the resistance to sorafenib. Arsenic trioxide (ATO) is a currently clinically used anticancer drug and displays its anticancer activities by inhibiting Akt activation. Therefore, we hypothesized that ATO may potentiate the anti-cancer activities of sorafenib against HCC. The results have demonstrated that ATO synergized with sorafenib to inhibit the proliferation and promote the apoptosis of HCC cells by diminishing the increased activation of Akt by sorafenib. ATO was shown to inhibit the expression or activation of Akt downstream factors, including glycogen synthase kinase (GSK)-3β, mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which regulate cell apoptosis and were upregulated or activated by sorafenib. Both sorafenib and ATO downregulated the expression of cyclin D1, resulting in HCC cells arrested at G0/G1 phase. ATO downregulated the expression of Bcl-2 and Bcl-xL and upregulated the expression of Bax, indicating that ATO could induce the apoptosis of HCC cells through the intrinsic pathways; but sorafenib showed little effects on these proteins of Bcl-2 family. ATO synergized with sorafenib to suppress the growth of HCC tumors established in mice by inhibiting the proliferation and inducing the apoptosis of HCC cells in situ. These results indicate that ATO may be a potential agent that given in combination with sorafenib acts synergistically for treating HCC.
KeywordsArsenic trioxide Sorafenib Hepatocellular carcinoma Akt Apoptosis Proliferation
This work was supported by grants from the National Natural Scientific Foundation of China (81172331, 81472321, and 81401975), and Heilongjiang Provincial Scientific Fund for Youths in China (QC2013C103 and QC2013C098).
Conflicts of interest
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