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
- 17.Alarifi S, Ali D, Alkahtani S, Siddiqui MA, Ali BA. Arsenic trioxide-mediated oxidative stress and genotoxicity in human hepatocellular carcinoma cells. Oncol Targets Ther. 2013;6:75–84.Google Scholar
- 20.Guilbert C, Annis MG, Dong Z, Siegel PM, Miller Jr WH, Mann KK. Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer. PLoS One. 2013;8:e85995. doi: 10.1371/journal.pone.0085995.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Xue P, Hou Y, Zhang Q, Woods CG, Yarborough K, Liu H, et al. Prolonged inorganic arsenite exposure suppresses insulin-stimulated AKT S473 phosphorylation and glucose uptake in 3T3-L1 adipocytes: involvement of the adaptive antioxidant response. Biochem Biophys Res Commun. 2011;407:360–5.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Serova M, de Gramont A, Tijeras-Raballand A, Dos Santos C, Riveiro ME, Slimane K, et al. Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib. Cancer Chemother Pharmacol. 2013;71:1297–307.CrossRefPubMedGoogle Scholar
- 36.Rahmani M, Aust MM, Attkisson E, Williams Jr DC, Ferreira-Gonzalez A, Grant S. Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process. Blood. 2012;119:6089–98.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Xargay-Torrent S, López-Guerra M, Montraveta A, Saborit-Villarroya I, Rosich L, Navarro A, et al. Sorafenib inhibits cell migration and stroma-mediated bortezomib resistance by interfering B-cell receptor signaling and protein translation in mantle cell lymphoma. Clin Cancer Res. 2013;19:586–97.CrossRefPubMedGoogle Scholar