title: Simultaneously targeting bcl-2 and Akt pathways sensitizes nasopharyngeal carcinoma to tumor necrosis factor-related apoptosis-inducing ligand.
abstract: The 5-year survival rate of nasopharyngeal carcinoma (NPC) is disappointing despite the much improved technologies in its treatment. Thus, finding more effective treatment for NPC has become an urgent priority. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in most tumor cells while sparing normal cells. However, its potential in the treatment of NPC has been limited by the eventual emergence of drug resistance. Bcl-2 and Akt contribute to TRAIL resistance in some cancer cells. In this study, CNE-2 was found to be the most resistant NPC cell line to TRAIL, and whether Bcl-2 small-interfering RNA (siRNA) and phosphatidylinositol 3-kinase (PI3-K) inhibitors (LY294002 and Wortmannin) could prevent TRAIL resistance in CNE-2 was also investigated. Results showed that both Bcl-2 siRNA and PI3-K inhibitors could prevent TRAIL resistance in CNE-2. Bcl-2 siRNA sensitized CNE-2 by activating the intrinsic apoptotic pathway and PI3-K inhibitors sensitized CNE-2 by activating both intrinsic and extrinsic pathways. Further, simultaneously targeting Bcl-2 and Akt was found to be a more efficient approach to prevent TRAIL resistance in CNE-2 and this synergistic effect happened at the level of Bid downstream. At last, the combinative treatments did not enhance toxicity of TRAIL in MRC5, a human benign fibroblast cell line. This study suggests that simultaneously targeting Bcl-2 and Akt pathway might be effective in preventing TRAIL resistance of NPC cells.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Shi-Sheng
authors.initials: SS
authors.lastname: Li
authors.forename: Qing-Lai
authors.initials: QL
authors.lastname: Tang
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D051057:Proto-Oncogene Proteins c-akt