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Cancer Gene Therapy (2012) 19, 489 -- 498& 2012 Nature America, Inc. All rights reserved 0929-1903/12
http://www.nature.com/
Web End =www.nature.com/cgt
ORIGINAL ARTICLE
Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1
W Ou1, S Ye1, W Yang, Y Wang, Q Ma, C Yu, H Shi, Z Yuan, G Zhong, J Ren, W Zhu and Y Wei
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 signicantly 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 signicant (Po0.01)
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 signicant (Po0.01)
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.
Cancer Gene Therapy (2012) 19, 489--498; doi:http://dx.doi.org/10.1038/cgt.2012.18
Web End =10.1038/cgt.2012.18 ; published online 11 May 2012
Keywords: cisplatin; combination therapy; LKB1; lung cancer
INTRODUCTIONNowadays, lung cancer is still the leading cause of cancer-related morbidity and mortality.1 Lung cancer metastasis is responsible for more than 90% of lung cancer-related death.2 Non-small-cell lung cancer (NSCLC) accounts for nearly 85% of all cases of lung cancer.3 It is estimated that lung cancer will continue to be a major health hurdle of mankind for the next 40--50 years.4
Cisplatin (cis-diamminedichloroplatinum) is a platinum-based agent, which has been wildly utilized in systemic therapeutic regimens for lung cancer, both NSCLC and small-cell lung cancer.5 Although the exact mechanisms of cisplatin-based antitumor...