Acta Pharmacologica Sinica (2009) 30: 467-477; doi: 10.1038/aps.2008.16

Acta Pharmacologica Sinica (2009) 30: 467-477; doi: 10.1038/aps.2008.16; published online 9th March 2009

Original Article

Enhancement of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying MDA-7/IL-24

Yu-mei WU¹, Kang-jian ZHANG¹, Xue-tian YUE¹, Yi-qiang WANG², Yi YANG¹, Gong-chu LI¹, Na LI¹, Yi-gang WANG^1,*

¹Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou 310018, China; ²Department of Surgery, Duchang People’s Hospital, Jiujiang 332600, China

Aim: The aim of this study was to creatively implement a novel chemo-gene-virotherapeutic strategy and further strengthen the antitumor effect in cancer cells by the combined use of ZD55-IL-24 and cisplatin.

Methods: ZD55-IL-24 is an oncolytic adenovirus that harbors interleukin 24 (IL-24), which has a strong antitumor effect and was identified and evaluated by PCR, RT-PCR, and Western blot analysis. Enhancement of cancer cell death using a combination of ZD55-IL-24 and cisplatin was assessed in several cancer cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cytopathic effect (CPE) assay. Apoptosis induction by treatment with ZD55-IL-24 and/or cisplatin was detected in BEL7404 and SMMC7721 by morphological evaluation, apoptotic cell staining, and flow cytometry analysis. In addition, negative effects on normal cells were evaluated in the L-02 cell line using the MTT assay, the CPE assay, morphological evaluation, apoptotic cell staining, and flow cytometry analysis.

Results: The combination of ZD55-IL-24 and cisplatin, which is superior to ZD55-IL-24, cisplatin, and ZD55-EGFP, as well as ZD55-EGFP plus cisplatin, resulted in a significantly increased effect. Most importantly, conjugation of ZD55-IL-24 with cisplatin had toxic effects equal to that of cisplatin and did not have overlapping toxicities in normal cells.

Conclusion: This study showed that ZD55-IL-24 conjugated with cisplatin exhibited a remarkably increased cytotoxic and apoptosis-inducing effect in cancer cells and significantly reduced the toxicity in normal cells through the use of a reduced dose.

Keywords: cisplatin; MDA-7/IL-24; oncolytic adenovirus; apoptosis

We thank Prof Xin-yuan LIU for his thorough review and approval of this article and Kan CHEN for her help with cell culture. This work was supported by the Zhejiang Science and Technology Support Plan (No 2007C 33027), National Natural Science Foundation of China (No 30800093, No 30801379), Science and Technology Commission of Shanghai Municipality (No 06DZ22032), National Basic Research Program of China (973 Program, No 2004 CB51804), Key Project of the Chinese Academy of Science (No KSCX2-YW-R-09, R-04), and Zhejiang Sci-Tech University Grant 0616033 to Prof Xin-yuan LIU.

* Correspondence to Dr Yi-gang WANG.
E-mail wangyigang43@163.com
Received 2008-10-21 Accepted 2009-01-31

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