Fighting cancer by triggering non-canonical mitochondrial permeability transition-driven necrosis through reactive oxygen species induction

• Published in: Free radical biology & medicine 2023-06, Vol.202, p.35-45
• Main Authors: Xiao, Qingwen, Zhong, Bingling, Hou, Ying, Wang, Miaojuan, Guo, Baojian, Lin, Ligen, Zhou, Yinning, Chen, Xiuping
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Death; Isobavachalcone; Mice; Mitochondria; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Transmembrane Permeability-Driven Necrosis; MPT-Driven necrosis; Necrosis; Neoplasms; Peptidyl-Prolyl Isomerase F - pharmacology; Permeability; Reactive Oxygen Species - metabolism; ROS
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.03.020

Non-apoptotic necrosis shows therapeutic potential for the treatment of various diseases, especially cancer. Mitochondrial permeability transition (MPT)-driven necrosis is a form of non-apoptotic cell death triggered by oxidative stress and cytosolic Ca2+ overload, and relies on cyclophilin D (CypD). Previous reports demonstrated that isobavachalcone (IBC), a natural chalcone, has anticancer effect by apoptosis induction. Here, we found that IBC induced regulated necrosis in cancer cells. IBC triggered non-apoptotic cell death in lung and breast cancer cells mediated by reactive oxygen species (ROS). IBC caused mitochondrial injury and dysfunction as evidenced by mitochondrial Ca2+ overload, the opening of MPT pore, mitochondrial membrane potential collapse, and structural damages. IBC-triggered cell death could be remarkably reversed by the ROS scavengers, cyclosporin A (CsA) and hemin, whereas CypD silence and heme oxygenase-1 overexpression failed to do so. Protein kinase B, dihydroorotate dehydrogenase, and mitogen-activated protein kinases were not involved in IBC-induced necrosis as well. In addition, IBC showed an anticancer effect in a 4T1 breast cancer cell-derived allograft mouse model, and this effect was considerably reversed by CsA. Collectively, our results showed that IBC triggered non-canonical MPT-driven necrosis mediated by ROS in cancer cells, which might provide a novel strategy for fighting against cancer. [Display omitted] •Isobavachalcone induced the mitochondrial permeability transition pore opening in cancer cells.•Isobavachalcone triggered MPT-driven necrosis-like cell death mediated by ROS.•Cyclosporin A abrogated the anticancer effects of Isobavachalcone both in vitro and in vivo.