Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo

摘要: The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that inhibits cellular proliferation and angiogenesis promotes apoptosis. However, underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared anti-proliferative properties in murine hepatoma cells syngeneic healthy hepatocytes vitro animal models HCC liver regeneration vivo. In vitro, demonstrate cell cycle activity expression anti-apoptotic Bcl-2 like proteins similarly downregulated by Hepa1-6 primary hepatocytes. Sorafenib-mediated activation caspase-3 induction apoptosis were exclusively found cells, but not matching We validated these findings vivo applying an isograft transplantation model partial hepatectomy (PH) C57BL/6 mice. treatment activated thus selectively small tumor foci originated from implanted surrounding Similarly, did induce after PH. transiently inhibited progression resulted mitotic catastrophe enhanced non-apoptotic injury during regeneration. Importantly, was associated p53-upregulated-modulator-of-apoptosis (PUMA). contrast, regenerating livers PH revealed downregulation PUMA completely protected conclude induces can additionally increase hepatocyte liver.