Smac mimetic and oleanolic acid synergize to induce cell death in human hepatocellular carcinoma cells. Issue 1 (28th August 2015)

• Record Type: Journal Article
• Authors: Liese, Juliane; Abhari, Behnaz Ahangarian; Fulda, Simone
• Is Part Of: Cancer letters. Volume 365:Issue 1(2015)
• Page Start: 47
• Page End: 56
• Publication Date: 2015-08-28
• Subjects: AIF apoptosis-inducing factor -- BSO Buthionine sulfoximine -- CAM chorioallantoic membrane -- cIAP cellular inhibitor of apoptosis -- DR5 death receptor-5 -- ENDOG endonuclease G -- ER endoplasmatic reticulum -- FCS fetal calf serum -- HBV hepatitis B virus -- HCC hepatocellular carcinoma -- HCV hepatitis C virus -- IAP inhibitor of apoptosis -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- NAC N-acetyl-cysteine -- NASH non-alcoholic fatty liver diseases -- Nec-1 necrostatin-1 -- OA oleanolic acid -- RFU relative fluorescence units -- RIP1 recepto r interacting protein 1 -- ROS reactive oxygen species -- Smac second mitochondria-derived activator of caspases -- SOD superoxide dismutase -- TRAIL tumor necrosis factor-related apoptosis-inducing ligand -- XIAP x-linked inhibitor of apoptosis -- zVAD.fmk N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; Cell death -- IAP proteins -- Smac -- Cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.04.018
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Synthetic lethal interaction of Smac mimetic and oleanolic acid in hepatocellular carcinoma. Cell death caused by combination treatment is ROS-dependent. Smac mimetic and oleanolic acid cooperate to suppress tumor growth in vivo . Abstract: Chemotherapy resistance of hepatocellular carcinoma (HCC) is still a major unsolved problem highlighting the need to develop novel therapeutic strategies. Here, we identify a novel synergistic induction of cell death by the combination of the Smac mimetic BV6, which antagonizes Inhibitor of apoptosis (IAP) proteins, and the triterpenoid oleanolic acid (OA) in human HCC cells. Importantly, BV6 and OA also cooperate to suppress long-term clonogenic survival as well as tumor growth in a preclinical in vivo model of HCC underscoring the clinical relevance of our findings. In contrast, BV6/OA cotreatment does not exert cytotoxic effects against normal primary hepatocytes, pointing to some tumor selectivity. Mechanistic studies show that BV6/OA cotreatment leads to DNA fragmentation and caspase-3 cleavage, while supply of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) revealed a cell type-dependent requirement of caspases for BV6/OA-induced cell death. The receptor interacting protein (RIP)1 kinase Inhibitor Necrostatin-1 (Nec-1) or genetic knockdown of RIP1 fails to rescue BV6/OA-mediated cell death, indicating that BV6/OA cotreatment does not primarily engage necroptotic cell death. Notably, the addition of several reactive oxygen species (ROS) scavengers significantly decreases BV6/OA-triggered cell death, indicating that ROS production contributes to BV6/OA-induced cell death. In conclusion, cotreatment of Smac mimetic and OA represents a novel approach for the induction of cell death in HCC and implicates further studies.