Mitochondria-Targeted Antibiotics toward Drug Resistant TNBC

Drug resistance is one of the greatest challenges in cancer treatment. Mitochondria play a crucial role in cell survival and death through the generation of reactive oxygen species (ROS). Recent research has shown that targeting mitochondria can promote tumor elimination, enhancing the effectiveness of strategies to combat drug resistance. In this context, we introduced a mitochondria-targeted antibiotic, compound 1 (CFX-TPP⁺). We found that 1 with its amide functional unit is much more stable in blood plasma than the compound with an ester group. Compound 1 also showed significant cytotoxicity toward drug resistant triple-negative breast cancer (TNBC) cells (MDA-MB-231). It enhances ROS generation, leading to increased mitochondrial oxidative stress and triggering a cascade of anticancer effects. These effects include the activation of mitochondria-mediated apoptotic cell signaling, upregulation of pro-apoptotic factors such as BAX, and downregulation of genes associated with mitochondrial biogenesis. This approach has the potential to overcome drug resistance in TNBC and possibly cure the disease without relapse.