101. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis
- Author
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Xue Kang Qi, Lin Feng, Lu Yang, Cheng Cheng Deng, Hui Qiong Han, Bing Chun Zhao, Qi Sheng Feng, Hao Jiong Zhang, Yi Fan Lian, Ling Gao, You Yuan Yao, Dajun Yang, Bo Hua Kuang, Jing Yuan, Li Zhen Chen, Ning Li, Yi Xin Zeng, Gui Ping He, Miao Xu, and Yu Chen Zhang
- Subjects
0301 basic medicine ,Cancer Research ,Time Factors ,Apoptosis ,Inhibitor of Apoptosis Proteins ,Antineoplastic Combined Chemotherapy Protocols ,Mice, Inbred BALB C ,Sulfonamides ,Nasopharyngeal Carcinoma ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,Azepines ,Tumor Burden ,Oncology ,Receptor-Interacting Protein Serine-Threonine Kinases ,Female ,RNA Interference ,Signal Transduction ,Cell Survival ,Nasopharyngeal neoplasm ,Mice, Nude ,Antineoplastic Agents ,Biology ,Inhibitor of apoptosis ,Transfection ,Mitochondrial Proteins ,03 medical and health sciences ,Inhibitory Concentration 50 ,Cell Line, Tumor ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Viability assay ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Dose-Response Relationship, Drug ,Tumor Necrosis Factor-alpha ,Carcinoma ,Molecular Mimicry ,Nasopharyngeal Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,stomatognathic diseases ,030104 developmental biology ,Nasopharyngeal carcinoma ,Drug Resistance, Neoplasm ,Cancer cell ,Cancer research ,Apoptosis Regulatory Proteins ,Proto-Oncogene Proteins c-akt - 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.
- Published
- 2016