Miriplatin-loaded liposome,as a novel mitophagy inducer,suppresses pancreatic cancer proliferation through blocking POLG and TFAM-mediated mtDNA replication  

作　　者：Xiaowei Wang Mengyan Wang Meilian Cai Rongguang Shao Guimin Xia Wuli Zhao 

机构地区：[1]State Key Laboratory of Respiratory Health and Multimorbidity,Key Laboratory of Antibiotic Bioengineering,Ministry of Health,Laboratory of Oncology,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Pharmaceutics Department,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第11期4477-4501,共25页药学学报（英文版）

基　　金：supported by grants from CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-002,2021-I2M-1030,China);National Natural Science Foundation of China (No.81473249 and 81102464);Drug Innovation Major Project of China (2018ZX09711001-007-002);National Key Research and Development Program of China (2016YFA0201504);National Mega-project for Innovative Drugs (2014ZX09201042,China)。

摘　　要：Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally different anti-cancer mechanism from previously reported platinum agents.Both in gemcitabine(GEM)-resistant/sensitive(GEM-R/S)pancreatic cancer cells,LMPt exhibits prominent anti-cancer activity,led by faster cellular entry-induced larger accumulation of MPt.The level of caveolin-1(Cav-1)determines entry rate and switch of entry pathways of LMPt,indicating a novel role of Cav-1 in nanoparticle entry.After endosome-lysosome processing,in unchanged metabolite,MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM,to degrade POLG and TFAM.Then,via PINK1-Parkin axis,mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA(mtDNA)replication blocking.Additionally,POLG and TFAM are identified as novel prognostic markers of pancreatic cancer,and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity.Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA(target of most platinum agents),and totally distinct mechanism of MPt and other formulations of MPt.Self-assembly offers LMPt special efficacy and mechanisms.Prominent action and characteristic mechanism make LMPt a promising cancer candidate.

关 键 词：Miriplatin-loaded liposome Pancreatic cancer Caveolae-mediated endocytosis Caveolin-1 MITOPHAGY Mitochondria DNA POLG TFAM 

分 类 号：R73[医药卫生—肿瘤]