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

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Pancreatic cancer presents a significant global health challenge due to high mortality rates and limited therapeutic options.
• Inducing pyroptosis, a form of inflammatory cell death, has emerged as a promising strategy to impede pancreatic ductal adenocarcinoma (PDAC) progression.

Purpose of the Study:

• To investigate the potential of Dronedarone hydrochloride (DH), an antiarrhythmic medication, as a pyroptosis inducer for pancreatic cancer therapy.
• To elucidate the mechanism by which DH induces pyroptosis and evaluate its efficacy in preclinical models of PDAC.

Main Methods:

• Utilized PANC-1 cells to assess DH-induced cell death and pyroptosis markers.
• Investigated DH's impact on mitochondrial stress and DNA leakage.
• Employed pyroptosis inhibitors and GSDMD silencing to confirm the pyroptosis pathway.
• Evaluated DH's anti-cancer effects in a murine model of pancreatic cancer.

Main Results:

• DH treatment resulted in dose- and time-dependent cell death in PANC-1 cells, specifically via GSDMD-dependent pyroptosis.
• DH elevated mitochondrial stress and induced mitochondrial DNA (mtDNA) release, activating the STING-cGAS pathway.
• In vivo studies demonstrated that DH significantly suppressed pancreatic tumor development in mice.

Conclusions:

• Dronedarone hydrochloride effectively triggers GSDMD-dependent pyroptosis in pancreatic cancer cells.
• DH's mechanism involves mitochondrial stress and subsequent activation of the STING-cGAS pathway.
• DH exhibits significant anti-PDAC growth potential, warranting further investigation as a therapeutic agent.