title: Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs.
abstract: The discovery of the TRAIL protein and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer therapies has yet to be established, as most cancer cells are TRAIL-resistant. In this report, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of c-FLIP expression and simultaneous inhibition of IAPs activity using AT406, a pan-antagonist of IAPs. Combined triple actions of the TRAIL, the IAPs inhibitor, AT406, and the c-FLIP expression inhibitor, rocaglamide (ART), markedly improve TRAIL-induced apoptotic effects in most solid cancer cell lines through the activation of an extrinsic apoptosis pathway. Furthermore, this ART combination does not harm normal cells. Among the 18 TRAIL-resistant cancer cell lines used, 15 cell lines become sensitive or highly sensitive to ART, and two out of three glioma cell lines exhibit high resistance to ART treatment due to very low levels of procaspase-8. This study provides a rationale for the development of TRAIL-induced apoptosis-based cancer therapies.
authors.affiliation: Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Tianrui
authors.initials: T
authors.lastname: Xu
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Yunlin
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Guanlin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
authors.forename: Kwen-Jen
authors.initials: KJ
authors.lastname: Chang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001392:Azocines / Q000008:administration & dosage; D001559:Benzhydryl Compounds / Q000008:administration & dosage; D001572:Benzofurans / Q000008:administration & dosage; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000627:therapeutic use; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D001392:Azocines; D001559:Benzhydryl Compounds; D001572:Benzofurans; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C107772:rocaglamide