Acta Pharmacologica Sinica 2007 December; 28 (12): 1996-2004; doi: 10.1111/j.1745-7254.2007.00672.x

Acta Pharmacologica Sinica 2007 December; 28 (12): 1996-2004; doi: 10.1111/j.1745-7254.2007.00672.x

Original Article

Enhanced sensitivity of hepatocellularcarcinoma cells to chemotherapy with a Smac-armed oncolytic adenovirus¹

Qiu-wei PAN^2,5, Su-yang ZHONG^2,5, Bi-sheng LIU², Jin LIU², Rong CAI², Yi-gang WANG², Xin-yuan LIU^2,3,4, Cheng QIAN^2,4

²Xin Yuan Institute of Medicine and Biotechnology, Life Science College, Zhejiang Sci-Tech University, Hangzhou 310018, China; ³Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Aim: The aim of the present study was to further improve the therapeutic effects for human hepatocellular carcinoma (HCC) and reduce the damage in normal cells using a novel chemo-gene-virotherapeutic strategy.

Methods: An oncolytic adenoviral vector (ZD55) similar to the typical oncolytic adenovirus ONYX-015, with a deletion of E1B-55K gene, was employed to express the second mitochondria-derived activator of caspases (Smac) protein by constructing a recombinant virus ZD55-Smac. The enhanced cytotoxicity of the combined treatment of ZD55-Smac with cisplatin or 5-fluorouracil (5-FU) was evaluated in several HCC cell lines. Moreover, the negative effects on normal cells have been tested in human normal liver cell lines L-02 and QSG-7701 cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptotic cell staining.

Results: According to our observation, ZD55-Smac is superior to ONYX-015 in sensitizing chemotherapy, ZD55-Smac used in conjunction with chemotherapy was found to exhibit obviously enhanced cytotoxicity in HCC cells, yet significantly abolished the negative toxicity in normal cells by utilizing the tumor selective replication vector and reducing the dosage.

Conclusion: This chemo-gene-virotherapeutic (cisplatin or 5-FU+ZD55-Smac) strategy is superior to the conventional chemo-gene or chemo-viro approach.

Keywords: oncolytic adenovirus; inhibitor of apoptosis proteins; second mitochondria-derived activator of caspases; chemotherapy; hepato- cellular carcinoma

¹This work was supported by the 973 Project (No 2004CB518804), the 863 project (No 20060102Z1107 ), the Zhejiang Provincial Grant (No 2006C23006), Zhejiang Funds for the Returned Students (No 116153A4I0538), and Zhejiang Natural Science Funds (No Y205282).

⁵These authors contributed equally to this paper.
⁴Correspondence to Prof Xin-yuan LIU and Prof Cheng QIAN.
Phn 86-571-8684-3181.
Fax 86-571-8684-3185.
E-mail xyliu@sibs.ac.cn (Xin-yuan LIU)
Phn 86-571-8684-3182.
Fax 86-571-8684-3185.
E-mail cqian3182@sina.com.cn (Cheng QIAN)
Received 2007-03-20 Accepted 2007-06-12

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