The actions of the multikinase inhibitor Sorafenib (Soraf) and its more potent fluoro-analog, Regorafenib (Regoraf) were examined on human Hep3B and PLC/PRF/5 hepatoma cells in vitro. IC50 was 7.5 µM for Soraf and 5.0 µM for Regoraf. Both agents required 48 hr. exposure to cells for maximal growth inhibitory effects measured by MTT at 96 hr. Evidence was found for Regoraf-induced apoptosis (max. 25% by FACS at 48 hr. and 45% decrease in Bcl-2 and BcL-xL), non-classical autophagy (50% increase in Beclin-1, without change in LC3 I/II ratio) and cell signaling changes (decreased p-ERK, increased p-JNK and p-Jun). In addition to growth inhibition, quiescence was observed for up to 6 wk. in the presence of prolonged drug exposure. Furthermore, after 1 wk. of drug-mediated inhibition, removal of either Soraf or Regoraf resulted in normal cell proliferation (recovery), unlike treatment with TGFβ 1µM or doxorubicin 0.1µM for 48 hr., after which no recovery was seen. The data are consistent with multiple mechanisms and pathways being altered during Regoraf-mediated growth inhibition and the induction of both quiescence and recovery after withdrawal of either Soraf or Regoraf, which have clinical implications.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2825. doi:1538-7445.AM2012-2825