α-Hederin Increases The Apoptosis Of Cisplatin-Resistant Gastric Cancer Cells By Activating Mitochondrial Pathway In Vivo And Vitro

OncoTargets and Therapy

关键词: α-Hederin;    Cisplatin–resistant gastric cancer cells;    Apoptosis;    Reactive oxygen species;    Mitochondrial pathway;   

DOI  :  

来源: DOAJ

【 摘 要 】

Yinghui Liu,1,2,* Hongbo Lei,3,* Jingjing Ma,1,2 Huan Deng,1,2 Pengzhan He,1,2 Weiguo Dong1 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China; 2Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China; 3Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiguo DongDepartment of Gastroenterology, Renmin Hospital of Wuhan University, No. 238 JieFang Road, Wuhan 430060, Hubei Province, People’s Republic of ChinaTel [phone]Fax [phone]Email [e-mail]: Gastric cancer remains an important cancer worldwide, and conventional chemotherapeutic drugs have the defects of drug resistance and cell toxicity. α-Hederin has been found to have certain therapeutic effects on various types of human cancers. However, studies on the α-hederin that exert biological activities on the cisplatin-resistant gastric cancer cells are limited. In this study, we evaluated the effects of α-hederin in HGC27/DDP and the potential mechanisms both in vivo and in vitro.Methods: HGC27/DDP cells were cultured in DMEM/F12 medium. Cell proliferation and viability were assessed quantitatively using Cell Counting Kit-8. Cell invasion and migration were detected by Transwell invasion assay and wound healing assay. Cell apoptosis was examined by employing Hoechst 33258 Staining Kit and an Annexin V-PE apoptosis kit. Intracellular GSH levels were examined by using a GSH Assay Kit. DCFH-DA and JC-1 Kit were used to detect levels of intracellular reactive oxygen species (ROS) and changes in mitochondrial membrane potential (∆Ψm). The protein levels of Apaf-1, AIF, Bax, Bcl-2, Cyt C, Survivin, cleaved caspase-3, cleaved caspase-9, MMP-9 and MMP-2 were detected by Western blot analysis. The effect of α-hederin in vivo was observed by xenograft tumor models in nude mice.Results: The α-hederin treatment significantly inhibited the proliferation in a dose- and time-dependent manner of HGC27/DDP and induced obvious apoptosis compared with the control group (P<0.05). Meanwhile, the ability of cells to invade and migrate was suppressed (P<0.05). The α-hederin induced the depletion of GSH (P<0.05) and the accumulation of intracellular ROS (P<0.05), changed the mitochondrial membrane potential (P<0.05), increased the Bax, Apaf-1, AIF, Cyt C, cleaved caspase-3 and cleaved caspase-9 expression and decreased the protein level of Bcl-2, survivin, MMP-9 and MMP-2 (P<0.05). Pretreatment with NAC (12 mM) enhanced the tendency and pretreatment with BSO (8 mM) attenuated the tendency above (P<0.05). Meanwhile, α-hederin inhibited xenograft tumor growth in vivo (P<0.05).Conclusion: Our study provides strong molecular evidence to support our hypothesis that α-hederin inhibits the proliferation and induces the apoptosis of HGC27/DDP cells by increasing the levels of intracellular ROS and triggering mitochondrial pathway activation.Keywords: α-hederin, cisplatin–resistant gastric cancer cells, apoptosis, reactive oxygen species, mitochondrial pathway

【 授权许可】

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