title: Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells.
abstract: We here evaluated the potential anti-colorectal cancer activity by erastin, a voltage-dependent anion channel (VDAC)-binding compound. Our in vitro studies showed that erastin exerted potent cytotoxic effects against multiple human colorectal cancer cell lines, possibly via inducing oxidative stress and caspase-9 dependent cell apoptosis. Further, mitochondrial permeability transition pore (mPTP) opening was observed in erastin-treated cancer cells, which was evidenced by VDAC-1 and cyclophilin-D (Cyp-D) association, mitochondrial depolarization, and cytochrome C release. Caspase inhibitors, the ROS scavenger MnTBAP, and mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid), as well as shRNA-mediated knockdown of VDAC-1, all significantly attenuated erastin-induced cytotoxicity and apoptosis in colorectal cancer cells. On the other hand, over-expression of VDAC-1 augmented erastin-induced ROS production, mPTP opening, and colorectal cancer cell apoptosis. In vivo studies showed that intraperitoneal injection of erastin at well-tolerated doses dramatically inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Together, these results demonstrate that erastin is cytotoxic and pro-apoptotic to colorectal cancer cells. Erastin may be further investigated as a novel anti-colorectal cancer agent.
authors.affiliation: Department of General Surgery, The Ninth People's Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Haizhong
authors.initials: H
authors.lastname: Huo
authors.affiliation: Department of General Surgery, The Ninth People's Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, The Ninth People's Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of General Surgery, The Ninth People's Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Wenyong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of General Surgery, The Ninth People's Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Ninth People's Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019073:HT29 Cells; D006801:Humans; D016513:Mice, SCID; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010879:Piperazines; D017382:Reactive Oxygen Species; C494762:VDAC1 protein, human; C477224:erastin; D050995:Voltage-Dependent Anion Channel 1; D053148:Caspase 3; D053453:Caspase 9