Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore.

Abstract

The permeability transition pore in mitochondria (MPTP) and the ATP-binding cassette transporters (АВС transporters) in cell membranes provide the efflux of low-molecular compounds across mitochondrial and cell membranes, respectively. The inhibition of ABC transporters, especially of those related to multi drug resistance (MDR) proteins, is an actively explored approach to enhance intracellular drug accumulation and increase thereby the efficiency of anticancer therapy. Although there is evidence showing the simultaneous effect of some inhibitors on both MDR-related proteins and mitochondrial functions, their influence on MPTP has not been previously studied. We examined the participation of verapamil and quinidine, classified now as the first generation of MDR modulators, and avermectin, which has recently been actively studied as an MDR inhibitor, in the regulation of the MPTP opening. In experiments on rat liver mitochondria, we found that quinidine lowered and verapamil increased the threshold concentrations of calcium ions required for MPTP opening, and that they both decreased the rate of calcium-induced swelling of mitochondria. These effects may be associated with the positive charge of the drugs and their aliphatic properties. Avermectin not only decreased the threshold concentration of calcium ions, but also by itself induced the opening of MPTP and the mitochondrial swelling inhibited by ADP and activated by carboxyatractyloside, the substrate and inhibitor of adenine nucleotide translocase (ANT), which suggests the involvement of ANT in the process. Thus, these data indicate an additional opportunity to evaluate the effectiveness of MDR modulators in the context of their influence on the mitochondrial-dependent apoptosis.