Synergistic Antitumor Effect Of Auy922 In Combination With Sorafenib In Hepatocellular Carcinoma Cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL PURPOSE: Molecularly targeted therapy is of particular importance for HCC due to a lack of efficacy with currently approved chemo-toxic therapies. It is of interest to investigate the combined effect of two molecular targeted drugs, sorafenib (a multi-kinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity) and a highly potent non-geldamycin HSP90 inhibitor, NVP-AUY922 on HCC treatment. EXPERIMENTAL DESIGNS: Cell viability after different treatments was measured by both 3,[4,5-dimethylthiazol-2-yl] -2,5-diphenyl-tetrazolium bromide (MTT) assay and cytofluorometric annexin-V apoptotic assay to compare the apoptotic cells induced by single versus combined treatment. Cell cycle analysis was also performed, and Western blotting was employed to determine the effects on MEK signaling, and in vivo efficacy was determined in nude mice with PLC/PRF/5 xenografts. RESULTS: Combined drugs treatment produced a synergistic effect on decreased HCC cell viability shown by MTT assay. An increase in the number of apoptotic cells were observed by apoptotic assay in combined drugs group when compared with single agents sorafenib or NVP-AUY922. Also, sorafenib combined with NVP-AUY922 induced S-phase arrest which was demonstrated by cell cycle analysis. Sorafenib alone decreases phospho-Erk1/2 expression, and this effect was further enhanced in combination treatment with NVP-AUY922. Finally, sorafenib plus NVP-AUY922 significantly suppressed PLC/PRF/5 xenograft tumor growth when compared with single (NVP-AUY922 or Sorafenib) treatment alone. CONCLUSION: The combination therapy of sorafenib and NVP-AUY922 can be a new and promising therapeutic approach to the treatment of HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2554. doi:10.1158/1538-7445.AM2011-2554