title: Self-complementary adeno-associated virus 5-mediated gene transduction of a novel CD40L mutant confers direct antitumor effects in lung carcinoma.
abstract: CD40 ligand (CD40L) gene therapy offers a potentially useful option for lung cancer due to its multiple antitumor activities. However, membrane-bound CD40L may be proteolytically cleaved to form soluble CD40L (sCD40L), which results in adverse effects. In a previous study by our group, it was demonstrated that recombinant self-complementary adeno-associated virus 5 (scAAV5) efficiently delivered genes to lung cancer cells. In the present study, an scAAV5 expressing a non-cleavable human CD40L mutant (scAAV5-CD40L-M) was generated and its direct antitumor effects in lung cancer were evaluated. Transduction with scAAV5-CD40L-M resulted in effective expression of CD40L on the cell surface with low levels of cleaved sCD40L, which significantly reduced the percentage of viable cells and promoted caspase-3-dependent apoptosis of CD40-positive lung carcinoma A549 cells, compared with scAAV5-CD40L transduction (P<0.05). Furthermore, treatment with scAAV5-CD40L-M exerted a significant antitumor effect against CD40-positive A549 xenografts by inducing apoptosis (P<0.05) with few side effects. Gene therapy using an scAAV5 vector expressing non-cleavable human CD40L mutant may therefore have direct antitumor effects against CD40-positive lung cancers. These tumoricidal effects of scAAV5-CD40L-M treatment make it a promising therapeutic technique for the treatment of lung cancer.
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Yaoxi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000235:genetics
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand