title: The mitochondrion interfering compound NPC-26 exerts potent anti-pancreatic cancer cell activity in vitro and in vivo.
abstract: The development of novel anti-pancreatic cancer agents is extremely important. Here, we investigated the anti-pancreatic cancer activity by NPC-26, a novel mitochondrion interfering compound. We showed that NPC-26 was anti-proliferative and cytotoxic to human pancreatic cancer cells, possibly via inducing caspase-9-dependent cell apoptosis. Pharmacological inhibition or shRNA-mediated silence of caspase-9 attenuated NPC-26-induced pancreatic cancer cell death and apoptosis. Further, NPC-26 treatment led to mitochondrial permeability transition pore (mPTP) opening in the cancer cells, which was evidenced by mitochondrial depolarization, ANT-1(adenine nucleotide translocator-1)-Cyp-D (cyclophilin-D) association and oxidative phosphorylation disturbance. mPTP blockers (cyclosporin and sanglifehrin A) or shRNA-mediated knockdown of key mPTP components (Cyp-D and ANT-1) dramatically attenuated NPC-26-induced pancreatic cancer cell apoptosis. Importantly, we showed that NPC-26, at a low concentration, potentiated gemcitabine-induced mPTP opening and subsequent pancreatic cancer cell apoptosis. In vivo, NPC-26 intraperitoneal injection significantly suppressed the growth of PANC-1 xenograft tumors in nude mice. Meanwhile, NPC-26 sensitized gemcitabine-mediated anti-pancreatic cancer activity in vivo. In summary, the results of this study suggest that NPC-26, alone or together with gemcitabine, potently inhibits pancreatic cancer cells possibly via disrupting mitochondrion.
authors.affiliation: Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian, 362000, China. yangyangfuzhou59@126.com.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Dong
authors.affiliation: Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian, 362000, China.
authors.forename: Yi-Huang
authors.initials: YH
authors.lastname: Zhuang
authors.affiliation: Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian, 362000, China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Cai
authors.affiliation: Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian, 362000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian, 362000, China.
authors.forename: Wen-Bing
authors.initials: WB
authors.lastname: Zou
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D033741:Adenine Nucleotide Translocator 1; D000970:Antineoplastic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; C580832:SLC25A4 protein, human; D003841:Deoxycytidine; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D021983:Cyclophilins; D000093542:Gemcitabine
keywords: Gemcitabine; Mitochondrion; NPC-26; Pancreatic cancer; mPTP