2. Academic Validation
  3. Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis

Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis

  • Cell Death Dis. 2024 Oct 2;15(10):725. doi: 10.1038/s41419-024-07102-w.
Ming-Qiao Li # 1 2 3 4,  Yu-Qi He # 1 2 3 4,  Meng-Ni Zhang # 1 2 3 4,  Wan Tang 1 2 3 4,  Ya Tan 1 2 3 4,  Yue Cheng 1 2 3 4,  Mei Yang 1,  Nan Zhao 1 2 3 4,  Ling Li 1 2 3 4,  Si-Rui Yu 1 2 3 4,  Ruo-Lan Li 1 2 3 4,  Qiong Pan 1 2 3 4,  Ming-Yue Wu 5 6 7 8,  Jin Chai 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 2 Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 3 Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 4 Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD), the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China.
  • 5 Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. wumingyue@xnyy.cn.
  • 6 Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, 400038, China. wumingyue@xnyy.cn.
  • 7 Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. wumingyue@xnyy.cn.
  • 8 Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD), the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China. wumingyue@xnyy.cn.
  • 9 Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. jin.chai@cldcsw.org.
  • 10 Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, 400038, China. jin.chai@cldcsw.org.
  • 11 Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. jin.chai@cldcsw.org.
  • 12 Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD), the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China. jin.chai@cldcsw.org.
  • # Contributed equally.
PMID: 39358349 DOI: 10.1038/s41419-024-07102-w
Abstract

Pancreatic Cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing Pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that Pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces Pyroptosis in pancreatic Cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only Pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent Pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and Pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic Cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers Pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.

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