title: Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma.
abstract: Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific α-fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Huei-Yue
authors.initials: HY
authors.lastname: Dai
authors.affiliation: Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Lai
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D024101:Mitochondrial Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C505371:MAVS protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000509:alpha-Fetoproteins; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D005472:Fluorouracil
keywords: combination therapy; hepatocellular carcinoma; metronomic chemotherapy; orthotopic animal model; synergistic antitumor effect