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Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

Cancer Gene Therapy volume 19, pages 489–498 (2012)Cite this article

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Abstract

LKB1 is a novel candidate tumor suppressor gene in lung cancer. In this study, we evaluated the effect of cationic liposomes (LPs)-mediated LKB1 gene (LPs-pVAX-LKB1) on low-dose cisplatin (cis-diamminedichloroplatinum)-mediated antitumor activity in lung cancer, both in vitro and in vivo. Our study demonstrated that cationic LPs-mediated LKB1 gene therapy could sensitize the response of lung cancer cells to cisplatin, and significantly induce apoptosis and inhibit proliferation, invasion and metastasis, compared with control groups. Combined treatment with intratumoral administration of Lps-pVAX-LKB1 and intraperitoneal injection of low-dose cisplatin into subcutaneous A549 lung tumor xenograft resulted in significant (P<0.01) inhibition of tumor growth. Furthermore, combined treatment with intravenous injections of Lps-pVAX-LKB1 and intraperitoneal injection of low-dose cisplatin into mice bearing experimental A549 lung metastasis demonstrated significant (P<0.01) decrease in the number of lung metastatic tumor nodules. Mice life spans of combination treatment group were also dramatically prolonged, compared with controls. Further studies indicated that LKB1-enhancing cisplatin-mediated antitumor effects might be associated with the upregulation of p-p53 and p-JNK, and downregulation of p-mammalian target of rapamycin, matrix metalloproteinase (MMP)-2 and MMP-9. This study suggests that the combination of LKB1 gene therapy with low-dose cisplatin-based chemotherapy may be a potent therapeutic strategy for lung cancer.

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Acknowledgements

This study was partly supported by the National Science and Technology Major Projects of New Drugs (2012ZX09103301-009). We thank Xiang Chen, Xiaolan Su, Yongqiu Mao and Qiaorong Huang (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University) for technical assistance.

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  1. W Ou and S Ye: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    W Ou, S Ye, W Yang, Y Wang, Q Ma, C Yu, H Shi, Z Yuan, G Zhong, J Ren, W Zhu & Y Wei

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  1. W Ou
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Correspondence to W Zhu.

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Ou, W., Ye, S., Yang, W. et al. Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1. Cancer Gene Ther 19, 489–498 (2012). https://doi.org/10.1038/cgt.2012.18

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