2. Academic Validation
  3. Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway

Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway

  • J Exp Clin Cancer Res. 2018 Mar 12;37(1):53. doi: 10.1186/s13046-018-0703-9.
Bao-Xia Li 1,  Heng-Bang Wang 2 3,  Miao-Zhen Qiu 4,  Qiu-Yun Luo 1,  Han-Jie Yi 1,  Xiang-Lei Yan 1,  Wen-Tao Pan 1,  Lu-Ping Yuan 1,  Yu-Xin Zhang 1,  Jian-Hua Xu 5,  Lin Zhang 6,  Da-Jun Yang 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 2 Department of Pharmacology, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, 350108, China.
  • 3 Ascentage Pharma Group Corp., Ltd., Taizhou, 225309, China.
  • 4 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
  • 5 Department of Pharmacology, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, 350108, China. xjh@fjmu.edu.cn.
  • 6 Departments of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China. zhanglin@sysucc.org.cn.
  • 7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. yangdj@sysucc.org.cn.
  • 8 Ascentage Pharma Group Corp., Ltd., Taizhou, 225309, China. yangdj@sysucc.org.cn.
PMID: 29530056 DOI: 10.1186/s13046-018-0703-9
Abstract

Background: Ovarian Cancer is a deadly disease. Inhibitors of Apoptosis proteins (IAPs) are key regulators of Apoptosis and are frequently dysregulated in ovarian Cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian Cancer.

Methods: CCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescence microscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFα protein. Caspase activity assay was used for Caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian Cancer cell xenograft nude mice model was used for in vivo efficacy evaluation.

Results: APG-1387 demonstrated potent inhibitory effect on ovarian Cancer cell growth and clonogenic cell survival. APG-1387 induced RIP1- and TNFα-dependent apoptotic cell death in ovarian Cancer through downregulation of IAPs proteins and induction of Caspase-8/FADD/RIP1 complex, which drives Caspase-8 activation. NF-κB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-κB activation. APG-1387 induced cytoprotective Autophagy while triggering Apoptosis in ovarian Cancer cells and inhibition of Autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian Cancer xenografts.

Conclusions: Our results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian Cancer.

Keywords

APG-1387; Apoptosis; Autophagy; Ovarian cancer.

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