Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 202, Issue -, Pages 35-45Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2023.03.020
Keywords
Isobavachalcone; ROS; Mitochondria; MPT-Driven necrosis
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Isobavachalcone (IBC), a natural chalcone, induces non-apoptotic cell death in lung and breast cancer cells mediated by reactive oxygen species (ROS), triggering non-canonical mitochondrial permeability transition-driven necrosis. This process relies on cyclophilin D (CypD) and could potentially be used as a novel strategy for cancer treatment.
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.
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