title: A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis.
abstract: Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC.
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Hui-Qiong
authors.initials: HQ
authors.lastname: Han
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Xue-Kang
authors.initials: XK
authors.lastname: Qi
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lian
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Bo-Hua
authors.initials: BH
authors.lastname: Kuang
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Zhang
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Deng
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Hao-Jiong
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: You-Yuan
authors.initials: YY
authors.lastname: Yao
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Gui-Ping
authors.initials: GP
authors.lastname: He
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Bing-Chun
authors.initials: BC
authors.lastname: Zhao
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Chen
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Ascentage Pharma Group Corp. Limited, Taizhou 225309, China. Electronic address: yangdj@sysucc.org.cn.
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Beijing Hospital, Beijing 100730, China. Electronic address: zengyx@sysucc.org.cn.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001381:Azepines / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000621546:APG-1387; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001381:Azepines; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: AKT; Apoptosis; NF-κB; Nasopharyngeal carcinoma; Smac mimetic