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

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Abstract

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.

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Acknowledgements

This work was 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) and the Excellent Research Program of Nanjing University (ZYJH004).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China

    Xin Yuan, Shuren Zhang, Xuanmeng Zhong, Hao Yuan, Dongfan Song, Xiaoyu Wang & Zijian Guo

  2. Department of Biomedical Engineering, College of Engineering and Applied Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China

    Hanyang Yu

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  1. Xin Yuan
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  2. Shuren Zhang
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  3. Xuanmeng Zhong
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Correspondence to Shuren Zhang or Zijian Guo.

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Supporting information The supporting information is available online at https://chem.scichina.com and https://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Yuan, X., Zhang, S., Zhong, X. et al. The induction of PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells by a multispecific platinum complex. Sci. China Chem. 65, 1978–1984 (2022). https://doi.org/10.1007/s11426-022-1314-3

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  • DOI: https://doi.org/10.1007/s11426-022-1314-3

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