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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.
AuthorsHuei-Yue Dai, Hui-Yu Chen, Wei-Chen Lai, Mien-Chie Hung, Long-Yuan Li
JournalOncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 23807-19 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
PMID26247632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BIK protein, human
  • MAVS protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • alpha-Fetoproteins
  • bcl-2-Associated X Protein
  • Doxorubicin
  • Fluorouracil
Topics
  • Adaptor Proteins, Signal Transducing (biosynthesis, genetics)
  • Animals
  • Apoptosis Regulatory Proteins (biosynthesis, genetics)
  • Carcinoma, Hepatocellular (drug therapy, genetics, pathology)
  • Cell Line, Tumor
  • Doxorubicin (pharmacology)
  • Enzyme Activation
  • Fluorouracil (pharmacology)
  • Humans
  • In Situ Nick-End Labeling
  • Liver Neoplasms (drug therapy, genetics, pathology)
  • Membrane Proteins (biosynthesis, genetics)
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Mitochondrial Proteins
  • Promoter Regions, Genetic (genetics)
  • Xenograft Model Antitumor Assays
  • alpha-Fetoproteins (genetics)
  • bcl-2-Associated X Protein (metabolism)

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