Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma

BMC Cancer

Research Article

Ikuo Sekine¹  Kenzo Hiroshima²  Koichiro Tatsumi³  Yuji Tada³  Hideaki Shimada⁴  Takao Morinaga⁵  Kiyoko Kawamura⁵  Yuanyuan Jiang⁶  Masatoshi Tagawa⁶  Boya Zhong⁶  Masato Shingyoji⁷ 

[1] Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan;Department of Surgery, School of Medicine, Toho University, Tokyo, Japan;Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, 260-8717, Chuo-ku, Chiba, Japan;Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, 260-8717, Chuo-ku, Chiba, Japan;Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan;Division of Respirology, Chiba Cancer Center, Chiba, Japan;

关键词: Mesothelioma;    Replication-competent adenovirus;    Bisphosphonates;    p53;   

DOI  :  10.1186/s12885-016-2483-y

 received in 2015-12-16, accepted in 2016-07-04,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundApproximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14ARF and the 16INK4A genes. Consequently, the majority of mesothelioma is defective of the p53 pathways. We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene.MethodsCytotoxicity of ZOL and Ad-delE1B55 was assessed with a WST assay. Cell cycle changes were tested with flow cytometry. Expression levels of relevant molecules were examined with western blot analysis to investigate a possible mechanism of cytotoxicity. Furthermore, the expressions of Ad receptors on target cells and infectivity were estimated with flow cytometry. Viral replication was assayed with the tissue culture infection dose method.ResultsA combinatory use of ZOL and Ad-delE1B55 suppressed cell growth and increased sub-G1 or S-phase populations compared with a single agent, depending on cells tested. The combinatory treatment up-regulated p53 levels and subsequently enhanced the cleavage of caspase-3, 8, 9 and poly (ADP-ribose) polymerase, but expression of molecules involved in autophagy pathways were inconsistent. ZOL-treated cells also increased Ad infectivity with a dose-dependent manner and augmented Ad replication although the expression levels of integrin molecules, one of the Ad receptors, were down-regulated.ConclusionsThese findings indicated that ZOL and Ad-delE1B55 achieved combinatory anti-tumor effects through augmented apoptotic pathways or increased viral replication.

【 授权许可】

CC BY   
© The Author(s). 2016