title: Reversal of the Apoptotic Resistance of Non-Small-Cell Lung Carcinoma towards TRAIL by Natural Product Toosendanin.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers cancer cell death via its association with death receptors on the cell membrane, but exerts negligible side effects on normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients exhibited resistance to TRAIL treatment in clinical trials, and the mechanism varies. In this study, we described for the first time that toosendanin (TSN), a triterpenoid derivative used in Chinese medicine for pain management, could significantly sensitize human primary NSCLC cells or NSCLC cell lines to TRAIL-mediated apoptosis both in vitro and in vivo, while showing low toxicity against human primary cells or tissues. The underlying apoptotic mechanisms involved upregulation of death receptor 5 (DR5) and CCAAT/enhancer binding protein homologous protein, which is related to the endoplasmic reticulum stress response, and is further associated with reactive oxygen species generation and Ca2+accumulation. Surprisingly, TSN also induced autophagy in NSCLC cells, which recruited membrane DR5, and subsequently antagonized the apoptosis-sensitizing effect of TSN. Taken together, TSN can be used to sensitize tumors and the combination of TRAIL and TSN may represent a useful strategy for NSCLC therapy; moreover, autophagy serves as an important drug resistance mechanism for TSN.
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Lab of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology and Intensive Care Unit, Changhai Hospital, Affiliated Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Jin
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Ri
authors.initials: R
authors.lastname: Zhou
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Zhao-Xin
authors.initials: ZX
authors.lastname: Zhang
authors.affiliation: Guang'anmen hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Baojin
authors.initials: B
authors.lastname: Hua
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Ji
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Cheng
authors.affiliation: College of Pharmacy, Nanjing University of Chinese medicine, China.
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Yin
authors.affiliation: Guang'anmen hospital, China Academy of Chinese Medical Sciences, Beijing, China.|Jiangsu Cancer Hospital &Institute Affiliated to Nanjing Medical University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Lab of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Yin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014315:Triterpenes
chemical_list: D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D002118:Calcium; D004365:Drugs, Chinese Herbal; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C036454:toosendanin; D014315:Triterpenes