Early effects of the antineoplastic agent salinomycin on mitochondrial function.

摘要: Salinomycin, isolated from Streptomyces albus, displays antimicrobial activity. Recently, a large-scale screening approach identified salinomycin and nigericin as selective apoptosis inducers of cancer stem cells. Growing evidence suggests that is able to kill different types non-stem tumor cells usually display resistance common therapeutic approaches, but the mechanism action this molecule still poorly understood. Since has been suggested act K+ ionophore, we explored its impact on mitochondrial bioenergetic performance at an early time point following drug application. In contrast ionophore valinomycin, induced rapid hyperpolarization. addition, matrix acidification significant decrease respiration were observed in intact mouse embryonic fibroblasts (MEFs) cell-like HMLE within tens minutes, while increased production reactive oxygen species was not detected. By comparing chemical structures cellular effects with those valinomycin (K+ ionophore) (K+/H+ exchanger), conclude mediates K+/H+ exchange across inner membrane. Compatible direct modulation function, induce cell death also Bax/Bak-less double-knockout MEF concentration range used most studies (around 10 μM) exerts effect level mitochondria alters performance, specificity pathologic B patients chronic lymphocytic leukemia (CLL) versus healthy subjects investigated. Mesenchymal stromal (MSCs), proposed mimic environment, attenuated apoptotic B-CLL Apoptosis occurred extent well MSCs human primary fibroblasts. The results indicate salinomycin, when above μM concentrations, direct, effects, thus compromising survival.