Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma

Huei-Yue Dai; Hui-Yu Chen; Wei-Chen Lai; Mien-Chie Hung; Long-Yuan Li

doi:10.18632/oncotarget.4278

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Research Papers:

Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma

Huei-Yue Dai _, Hui-Yu Chen, Wei-Chen Lai, Mien-Chie Hung and Long-Yuan Li

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Oncotarget. 2015; 6:23807-23819. https://doi.org/10.18632/oncotarget.4278

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Abstract

Huei-Yue Dai1, Hui-Yu Chen2, Wei-Chen Lai2, Mien-Chie Hung1,2,3,4, Long-Yuan Li1,2,3

1Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan

2Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

3Department of Biotechnology, Asia University, Taichung 413, Taiwan

4Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Long-Yuan Li, e-mail: [email protected]

Mien-Chie Hung, e-mail: [email protected]

Keywords: synergistic antitumor effect, combination therapy, orthotopic animal model, hepatocellular carcinoma, metronomic chemotherapy

Received: March 24, 2015 Accepted: June 05, 2015 Published: June 17, 2015

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.

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Research Papers:

Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma

Abstract