title: Smac mimetics in combination with TRAIL selectively target cancer stem cells in nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colony- and sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma.
authors.affiliation: Corresponding Authors: Yi-Xin Zeng, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China. zengyx@sysucc.org.cn.
authors.forename: Man-Si
authors.initials: MS
authors.lastname: Wu
authors.forename: Guang-Feng
authors.initials: GF
authors.lastname: Wang
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.forename: Heng-Bang
authors.initials: HB
authors.lastname: Wang
authors.forename: Miao-Yi
authors.initials: MY
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Min
authors.forename: Li-zhen
authors.initials: LZ
authors.lastname: Chen
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.forename: Jin-Xin
authors.initials: JX
authors.lastname: Bei
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001392:Azocines / Q000494:pharmacology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002277:Carcinoma; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000737:chemistry; D018716:Molecular Mimicry; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D001392:Azocines; D001559:Benzhydryl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; C533467:SM 164; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014230:Triazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases