2. Academic Validation
  3. Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

  • Front Pharmacol. 2021 Jul 8:12:670081. doi: 10.3389/fphar.2021.670081.
Liang Yan 1,  Yi Liu 2,  Xue-Feng Ma 3,  Dan Hou 2 4,  Yu-Hui Zhang 2,  Yong Sun 1,  Shan-Shan Shi 3,  Tim Forouzanfar 4,  Hai-Yan Lin 5,  Jun Fan 1,  Gang Wu 4 6
Affiliations

Affiliations

  • 1 Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, China.
  • 2 Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 4 Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC/VUmc Location and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universitetit Amsterdam, Amsterdam Movement Science, Amsterdam, Netherlands.
  • 5 Savaid Stomatology School, Hangzhou Medical College, Hangzhou, China.
  • 6 Department of Oral Implantology and Prosthetic Dentistry, Academic Centre of Dentistry Amsterdam (ACTA), Universiteit van Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
PMID: 34305590 DOI: 10.3389/fphar.2021.670081
Abstract

Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in Cancer cells, which can be induced by activated Caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast Cancer cells. In this study, to test the function of triclabendazole on breast Cancer, we treated breast Cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of Pyroptosis. Triclabendazole activates Apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of Caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/Pyroptosis is further induced by active Caspase-3. Consistent with this, triclabendazole-induced GSDME-N-terminal fragment cleavage and Pyroptosis were reduced by caspase-3-specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced Reactive Oxygen Species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent Pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of Caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent Pyroptosis by Caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in Cancer treatment.

Keywords

breast cancer; caspase-3; gasdermin E; pyroptosis; triclabendazole.

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