Selective mitochondrial dysfunction and redox collapse induced by an indole chalcone in breast cancer cells

Breast cancer (BC) is a major health concern and remains one of the most frequently diagnosed malignancies among women worldwide. The metabolism of tumour cells, particularly their energy metabolism and ability to adapt to changing environmental conditions, has long been a focus of research. We previously reported that the synthetic chalcone derivative ZK-CH-11d (11d) induces apoptosis through the mitochondrial pathway. In this study, we demonstrate a significant and selective effect of 11d on the energy metabolism of tumour cells, without affecting non-cancer cells. We highlight alterations in mitochondrial metabolism associated with changes in mitochondrial function and the morphology of the mitochondrial network. Our results show that exposure to the 11d chalcone reduces mitochondrial potential in tumour cells, activates respiratory chain complex I, induces massive reactive oxygen species (ROS) production, inhibits respiration, alters mitochondrial morphology, and modulates markers of oxidative and carbonyl stress. Importantly, we observed a breakdown of the mitochondrial network, indicative of a loss of metastatic potential in triple-negative MDA-MB-231 cells. Our aim was not to eliminate cancer cells directly but to understand the mechanism of action of the compound 11d, which triggers apoptotic processes.