title: Adenovirus-mediated TRAIL expression and downregulation of Bcl-2 expression             suppresses non-small cell lung cancer growth in vitro and in vivo.
abstract: Primary or acquired resistance to current treatment methods remains a major factor in clinical oncology and may be caused by failures in apoptosis programs. TNF-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in several human cancer cell types. However, not all cancer cells are susceptible to TRAIL and mechanisms of resistance and new strategies to enhance sensitivity are an area of intense investigation. Therefore, we investigated whether TRAIL resistance is due to Bcl-2 levels. In this study, we generated an adenoviral vector, Ad5.TRAIL/siBcl2, that permitted co-expression of shRNA against Bcl-2 and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapeutic gene from a cytomegalovirus promoter. Infection with Ad5.TRAIL/siBcl2 resulted in significant cytotoxicity in non-small cell lung cancer (NSCLC) cells in vitro. In contrast, it had no effect on a normal lung cell line, WI-38. Impressively, treatment of the established NSCLC tumor model with Ad5.TRAIL/siBcl2 resulted in significant tumor regression, compared with other adenoviruses. This potent antitumor activity induced by Ad5.TRAIL/siBcl2 was due to strong inhibition of Bcl-2 and high expression of TRAIL. Thus, this study may provide a framework for future clinical applications of Ad5.TRAIL/siBcl2 in lung tumor gene therapy.
authors.affiliation: Department of Clinical Laboratory, The Affiliated Hospital of                     Qingdao University Medical College, Qingdao 266003, P.R. China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Zhang
authors.forename: Aihua
authors.initials: A
authors.lastname: Sui
authors.forename: Zhenli
authors.initials: Z
authors.lastname: Wang
authors.forename: Shihai
authors.initials: S
authors.lastname: Liu
authors.forename: Ruyong
authors.initials: R
authors.lastname: Yao
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand