Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a...

To effectively trigger an energy crisis within cancer cells, we devised and synthesized mitochondria-targeted catechol-based diphenylpolyenes by coupling them with a triphenylphosphonium unit via a modular synthetic approach. The exploration of structure-activity relationships in terms of cytotoxicity discloses that Mito-DHH, a catechol-type diphenylhextriene that specifically targets mitochondria, is the most potent molecule among those tested, manifesting its preferential elimination of A549 cells (IC₅₀ = 0.25 μM) as opposed to normal L02 cells (IC₅₀ = 2.8 μM). In this regard, it outperforms doxorubicin and 5-fluorouracil, the commonly employed chemotherapy drugs. Mechanistic investigation affirms that the rapid accumulation of Mito-DHH within mitochondria of A549 cells enables its efficient auto-oxidation by leveraging the alkaline mitochondrial matrix to effectively and selectively generate reactive oxygen species (ROS). Through the generation of ROS, Mito-DHH initiates a ROS-dependent reduction of ATP levels within A549 cells in a dual-effect inhibitory pattern against both mitochondrial and glycolytic metabolisms, and the ultimate and selective apoptosis of A549 cells. This study takes Mito-DHH as an example to emphasize the universality of a ROS-generating strategy by targeting mitochondria in effectively inducing an energy crisis within cancer cells.