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

• Published in: Cell death & disease 2024-10, Vol.15 (10), p.725-10, Article 725
• Main Authors: Li, Ming-Qiao, He, Yu-Qi, Zhang, Meng-Ni, Tang, Wan, Tan, Ya, Cheng, Yue, Yang, Mei, Zhao, Nan, Li, Ling, Yu, Si-Rui, Li, Ruo-Lan, Pan, Qiong, Wu, Ming-Yue, Chai, Jin
• Format: Article
• Language: English
• Subjects: 14/19; 14/34; 42/89; 631/154/436; 631/80/82; 64/60; 692/699/67/1504; 82/1; 82/29; Adenocarcinoma; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Dronedarone - pharmacology; Humans; Immunology; Life Sciences; Mice; Mice, Nude; Mitochondrial DNA; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pyroptosis; Pyroptosis - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07102-w

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.