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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.Cancer Gene Therapy advance online publication, 8 March 2013; doi:10.1038/cgt.2013.14.
Cancer gene therapy 03/2013; · 3.13 Impact Factor
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ABSTRACT: Radiotherapy is the common treatment of choice for locally advanced lung cancer, but the radioresistance of lung cancer remains a significant therapeutic obstacle. We previously demonstrated that adenovirus-mediated inhibitor of growth 4 (ING4) tumor suppressor gene delivery (AdVING4) can chemosensitize human hepatocarcinoma cells to anticancer drug cisplatin (CDDP). However, its radiosensitizing effects in cancer therapy are largely elusive. In the present study, we investigated the therapeutic efficacy of AdVING4 gene therapy combined with ionizing radiotherapy for SPC-A1 human non-small-cell lung cancer (NSCLC) cells in vitro and in vivo in athymic nude mice, and also elucidated its underlying mechanisms. We found that AdVING4 gene therapy plus radiotherapy induced synergistic tumor suppression and apoptosis in in vitro SPC-A1 human NSCLC cells and in vivo SPC-A1 xenografted tumors s.c. implanted in athymic nude mice. Mechanistically, AdVING4 combined with radiation resulted in a substantial upregulation of Bax, Fas, FasL and Cleaved Caspase-3, and downregulation of Bcl-2 in SPC-A1 human NSCLC xenografted tumors. In addition, AdVING4 plus radiation synergistically reduced the tumor vessel CD34 expression and microvessel density (MVD) in vivo. Most importantly, AdVING4 potentially blocked the radiation-induced enhancement of cyclooxygenase-2 and survivin radioresistant factors, and vascular endothelial growth factor and IL-8 proangiogenic factors. The enhanced antitumor effects elicited by AdVING4 plus radiotherapy were closely associated with the cooperative activation of intrinsic and extrinsic apoptotic pathways, and synergistic inhibition of tumor angiogenesis. Thus, our results suggested that AdVING4 combined with radiotherapy may be a feasible and effective strategy for treatment of radioresistant NSCLC and other cancers.
Cancer gene therapy 08/2012; 19(10):697-706. · 3.13 Impact Factor
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ABSTRACT: ING4 as a member of inhibitor of growth (ING) tumor suppressor family has potent inhibitory effects on a variety of tumors. Interleukin-24 (IL-24), a cytokine-tumor suppressor, also shows broad-spectrum and tumor-specific antitumor activities. In this report, we constructed an ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) and assessed its combined effect on in vitro and in vivo A549 human non-small cell lung cancer cells. We demonstrated that ING4 and IL-24 combination treatment by adenovirus-mediated ING4 and IL-24 coexpression induced additive growth suppression and apoptosis as well as an overlapping effect on upregulation of P21, P27, Fas, Bax and cleaved Caspases-8, 9, 3 and downregulation of Bcl-2 in in vitro A549 lung carcinoma cells. Moreover, Ad-ING4-IL-24 treatment additively inhibited in vivo A549 lung carcinoma subcutaneous (s.c.) xenografted tumor growth and reduced CD34 and microvessel density in A549 xenografted tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-ING4-IL-24 was closely associated with the coordinate activation of extrinsic and intrinsic apoptotic pathways and additive inhibition of tumor angiogenesis. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as ING4 and IL-24 may constitute a novel and effective therapeutic strategy for lung carcinoma and other cancers.
Cancer gene therapy 06/2011; 18(9):627-36. · 3.13 Impact Factor
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ABSTRACT: The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of the ING family has potential tumor-suppressive effects. In this study, we explored the combined effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer plus chemotherapy drug cisplatin (CDDP) on SMMC-7721 human hepatocarcinoma cells in vitro and in vivo, and its underlying mechanism. We demonstrated that Ad-ING4 plus CDDP induced synergistic growth inhibition, enhanced apoptosis, and had an additive effect on upregulation of Fas, Bax, Bak, cleaved Bid, cleaved caspase-8, caspase-9, caspase-3 and cleaved PARP, and on downregulation of Bcl-2 and Bcl-X(L) in SMMC-7721 hepatocarcinoma cells. Moreover, Ad-ING4 plus CDDP synergistically suppressed in vivo SMMC-7721 hepatocarcinoma subcutaneous (s.c.) xenografted tumor growth and reduced tumor vessel CD34 expression and microvessel density (MVD) in athymic nude mice. Most importantly, Ad-ING4 plus CDDP did not have overlapping toxicities in HL-7702 normal human liver cells and normal liver tissues of mice. The in vitro and in vivo enhanced antitumor effect elicited by Ad-ING4 plus CDDP was closely associated with the cooperative regulation of extrinsic and intrinsic apoptotic pathways and synergistic inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 plus CDDP is a potential combined treatment strategy for hepatocarcinoma.
Cancer gene therapy 11/2010; 18(3):176-88. · 3.13 Impact Factor
