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Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer

Cancer Gene Therapy volume 20, pages 251–259 (2013)Cite this article

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Abstract

DNA-damaging anticancer drug cisplatin (cis-diamminedichloroplatinum) (DDP)-based chemotherapy is the mainstay and standard treatment for small-cell lung cancer (SCLC). However, frequent relapse and chemoresistance of SCLC remains a significant therapeutic hurdle. Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as a negative regulator of phosphoinositide 3-kinase/AKT survival pathway exhibits strong tumor-suppressive activities. A combination of chemotherapy and gene therapy (chemogene therapy) is a promising practice in cancer therapy. In this report, we examined the combined antitumor effect of adenovirus-mediated PTEN (AdVPTEN) gene therapy and DDP chemotherapy on PTEN-null NCI-H446 human SCLC cells in vitro and in vivo in athymic BALB/c nude mice. We demonstrated that AdVPTEN plus DDP enhanced growth suppression, cell-cycle G1 phase arrest and apoptosis in in vitro NCI-H446 tumor cells and in vivo NCI-H446 xenografted tumors subcutaneously inoculated in nude mice. Mechanistically, AdVPTEN plus DDP exerted an overlapping effect on upregulation of P53, P21, P27, Bax and Cleaved Caspase-3 as well as downregulation of Bcl-2 and survivin in in vitro and in vivo NCI-H446 tumor cells. Moreover, AdVPTEN plus DDP additively reduced tumor vessel CD34 expression and microvessel density in vivo. The enhanced therapeutic efficacy elicited by AdVPTEN plus DDP was closely associated with additive induction of G1 phase arrest and apoptosis via substantially modulating cell-cycle regulation molecules and activating intrinsic apoptotic pathway through P53 restoration, and overlapping inhibition of tumor angiogenesis. Thus, our results indicated that AdVPTEN combined with DDP may be a novel and effective chemogene therapy modality for human SCLC.

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Acknowledgements

This research work was supported by grants from the National Natural Science Foundation of China (No. 81001016), Medicine Research Foundation of Jiangsu Provincial Public Health Department (No. H200914) and Clinical Medicine Special Foundation of Jiangsu Provincial Science and Technology Department (No. BL2012023).

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  1. D Li and Y Zhang: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China

    D Li & Y Zhu

  2. Institute for Fetal Origin Diseases and Reproductive Medicine Center, the First Affiliated Hospital and Experiment Center of Soochow University, Suzhou, China

    Y Zhang

  3. Department of Cell and Molecular Biology, College of Medicine, Soochow University, Suzhou, China

    Y Xie & J Yang

  4. Department of Oncology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Y Xie & J Xiang

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Correspondence to Y Zhu or J Yang.

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Li, D., Zhang, Y., Xie, Y. et al. Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer. Cancer Gene Ther 20, 251–259 (2013). https://doi.org/10.1038/cgt.2013.14

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