The induction of PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells by a multispecific platinum complex  

作　　者：Xin Yuan Shuren Zhang Xuanmeng Zhong Hao Yuan Dongfan Song Xiaoyu Wang Hanyang Yu Zijian Guo 

机构地区：[1]State Key Laboratory of Coordination Chemistry,School of Chemistry and Chemical Engineering,Chemistry and Biomedicine Innovation Center(ChemBIC),Nanjing University,Nanjing 210023,China [2]Department of Biomedical Engineering,College of Engineering and Applied Sciences,Chemistry and Biomedicine Innovation Center(ChemBIC),Nanjing University,Nanjing 210023,China

出　　处：《Science China Chemistry》2022年第10期1978-1984,共7页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China (21731004,91953201,21907050,22107047);the Natural Science Foundation of Jiangsu Province (BK20202004);the Postdoctoral Research Funding Program of Jiangsu Province (003503);the Excellent Research Program of Nanjing University (ZYJH004)

摘　　要：Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma(PDAC) cells to a state that is awfully resistant to apoptosis.An alternative coping strategy is to trigger a nonapoptotic cell death.Herein,a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin.Interestingly,SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis,apoptosis and necroptosis,similar to PANoptosis(a newfound inflammatory cell death).Mechanistically,SEP could enter cancer cells effectively,then damage nuclear DNA,boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor metabolism.To our best knowledge,SEP is the first metal complex,even small molecule,to elicit PANoptosis(pyroptosis,apoptosis and necroptosis) in cancer cells,providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.

关 键 词：metallodrug pancreatic ductal adenocarcinoma PANoptosis cell death platinum prodrug 

分 类 号：R735.9[医药卫生—肿瘤]