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盐酸决奈达隆（DH）通过触发线粒体DNA介导的细胞焦亡诱导胰腺癌细胞死亡。

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

作者信息

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

机构信息

Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China.

Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, 400038, China.

出版信息

Cell Death Dis. 2024 Oct 2;15(10):725. doi: 10.1038/s41419-024-07102-w.

DOI:10.1038/s41419-024-07102-w
PMID:39358349
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11447222/
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.

摘要

胰腺癌是癌症相关死亡的主要原因之一，治疗方法欠佳。先前的研究表明，诱导胰腺导管腺癌（PDAC）发生细胞焦亡可减缓PDAC的生长，这意味着细胞焦亡诱导剂可能对PDAC治疗有效。在此，我们发现抗心律失常药物盐酸决奈达隆（DH）可诱导胰腺癌细胞发生细胞焦亡，并抑制小鼠体内PDAC的发展。在PANC-1细胞中，DH以剂量和时间依赖性方式导致细胞死亡，只有细胞焦亡抑制剂和GSDMD沉默可挽救细胞死亡，这表明DH触发了GSDMD依赖性细胞焦亡。进一步的研究表明，DH增加了线粒体应激并导致线粒体DNA（mtDNA）泄漏，激活了胞质中的STING-cGAS和细胞焦亡途径。最后，我们在胰腺癌小鼠模型中评估了DH的抗癌作用，发现DH治疗可在体内抑制胰腺肿瘤的发展。总的来说，我们的研究表明DH可触发PDAC中的细胞焦亡，并提出了其对抑制PDAC生长的潜在作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4d9/11447222/a861ee438fec/41419_2024_7102_Fig7_HTML.jpg
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