title: Pre-clinical evaluation of cinobufotalin as a potential anti-lung cancer agent.
abstract: Lung cancer is a major cause of cancer-related mortality in the United States and around the world. Due to the pre-existing or acquired chemo-resistance, the current standard chemotherapy regimens only show moderate activity against lung cancer. In the current study, we explored the potential anti-lung cancer activity of cinobufotalin in vivo and in vitro, and studied the underlying mechanisms. We demonstrated that cinobufotalin displayed considerable cytotoxicity against lung cancer cells (A549, H460 and HTB-58 lines) without inducing significant cell apoptosis. Our data suggest that mitochondrial protein cyclophilin D (Cyp-D)-dependent mitochondrial permeability transition pore (mPTP) opening mediates cinobufotalin-induced non-apoptotic death of lung cancer cells. The Cyp-D inhibitor cyclosporine A (CsA), the mPTP blocker sanglifehrin A (SfA), and Cyp-D shRNA-silencing significantly inhibited cinobufotalin-induced mitochondrial membrane potential (MMP) reduction and A549 cell death (but not apoptosis). Using a mice xenograft model, we found that cinobufotalin inhibited A549 lung cancer cell growth in vivo. Thus, cinobufotalin mainly induces Cyp-D-dependent non-apoptotic death in cultured lung cancer cells. The results of this study suggest that cinobufotalin might be further investigated as a novel anti-lung cancer agent.
authors.affiliation: Department of Geriatrics, Shanghai Changning Center Hospital, Shanghai 200336, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Kai
authors.affiliation: Department of Geriatrics, Shanghai Changning Center Hospital, Shanghai 200336, China.
authors.forename: Jia-Huan
authors.initials: JH
authors.lastname: Lu
authors.affiliation: Department of Geriatrics, Shanghai Changning Center Hospital, Shanghai 200336, China.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Hui
authors.affiliation: Department of Geriatrics, Shanghai Changning Center Hospital, Shanghai 200336, China. Electronic address: huizhaovip@126.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002018:Bufanolides / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D000081406:Peptidyl-Prolyl Isomerase F; D007783:Lactones; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D034741:RNA, Small Interfering; D013141:Spiro Compounds; C121329:sanglifehrin A; D016572:Cyclosporine; D021983:Cyclophilins; C063451:cinobufotalin
keywords: Cell death; Cinobufotalin; Cyclophilin D; Lung cancer; Mitochondrial permeability transition pore (mPTP)