title: Enhanced therapeutic efficacy of adenovirus-mediated interleukin-24 gene therapy combined with ionizing radiotherapy for nasopharyngeal carcinoma.
abstract: Melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24), a unique cytokine tumor suppressor, displays ubiquitous antitumor activities and cancer-specific cytotoxicities via multiple signaling pathways. In the present study, we investigated the antitumor effect of adenovirus-mediated IL-24 (AdVIL-24) gene therapy in conjunction with ionizing radiation on CNE-2Z human nasopharyngeal carcinoma (NPC) cells in vitro and in vivo in athymic nude mice, and its potential mechanisms. We demonstrated that AdVIL-24 gene therapy plus ionizing radiotherapy induced enhanced growth inhibition, cell cycle G1 phase arrest and apoptosis in vitro in CNE-2Z human NPC cells and in vivo in CNE-2Z xenografted tumors subcutaneously implanted in athymic nude mice. Mechanistically, AdVIL-24 combined with ionizing radiation led to the substantial upregulation of P21 and P27 cyclin-dependent kinase (CDK) inhibitors, ratio of pro-apoptotic to anti-apoptotic molecules Bax/Bcl-2 and cleaved caspase‑3 as well as downregulation of cyclin E and CDK2 in vitro and in vivo in CNE-2Z human NPC cells. Furthermore, AdVIL-24 plus radiation additively reduced the tumor vessel CD34 expression and microvessel density in vivo. More importantly, AdVIL-24 potentially blocked the radiation-induced enhancement of vascular endothelial growth factor (VEGF), a pro-angiogenic factor. The enhanced antitumor activity against NPC elicited by AdVIL-24 gene therapy combined with ionizing radiotherapy was closely associated with the enhanced induction of G1 phase arrest and apoptosis via additive modulation of cell cycle regulatory molecules and activation of intrinsic apoptotic pathways, and the overlapping inhibition of tumor angiogenesis. Thus, our results suggest that AdVIL-24 gene therapy combined with ionizing radiotherapy may be a novel and effective treatment strategy for human NPC.
authors.affiliation: Department of ENT, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Liu
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
authors.forename: Jicheng
authors.initials: J
authors.lastname: Yang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002277:Carcinoma; D053148:Caspase 3; D002453:Cell Cycle; D049109:Cell Proliferation; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D005720:Gamma Rays / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007124:Immunoenzyme Techniques; D007378:Interleukins / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D011878:Radiotherapy; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D014408:Biomarkers, Tumor; D053148:Caspase 3; D003037:Cobalt Radioisotopes; D007378:Interleukins; D012333:RNA, Messenger; D000099180:Interleukin-24