Makako Yamanaka1, Yuji Tada2, Kiyoko Kawamura3, Quanhai Li4, Shinya Okamoto5, Kuan Chai6, Sana Yokoi7, Min Liang8, Toshihiko Fukamachi5, Hiroshi Kobayashi5, Naoto Yamaguchi9, Atsushi Kitamura2, Hideaki Shimada10, Kenzo Hiroshima11, Yuichi Takiguchi12, Koichiro Tatsumi2, Masatoshi Tagawa13. 1. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Respirology, Chiba University, Chiba, Japan. 2. Department of Respirology, Chiba University, Chiba, Japan. 3. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan. 4. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Molecular Biology and Oncology, Chiba University, Chiba, Japan. 5. Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. 6. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. 7. Division of Translational Genomics, Chiba Cancer Center Research Institute, Chiba, Japan. 8. TOT Shanghai RD Center, Shanghai, China. 9. Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. 10. Department of Surgery, School of Medicine, Toho University, Tokyo, Japan. 11. Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan. 12. Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. 13. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Molecular Biology and Oncology, Chiba University, Chiba, Japan. Electronic address: mtagawa@chiba-cc.jp.
Abstract
INTRODUCTION: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways. METHODS: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents. RESULTS: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model. CONCLUSIONS: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.
INTRODUCTION: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways. METHODS: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents. RESULTS: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model. CONCLUSIONS: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.