Cyclosporine A enables vincristine-induced apoptosis during reversal of multidrug resistance phenotype in chronic myeloid leukemia cells

Abstract

Multidrug resistance (MDR) is considered a multifactorial phenotype which prevents a successful clinical cancer treatment. This phenomenon is mainly associated with mechanisms that include drug extrusion by P-glycoprotein (Pgp) overexpression and resistance to apoptosis derived by members of the inhibitor of apoptosis proteins (IAPs), such as XIAP. Studies have proposed the use of compounds that are able to inhibit or modulate Pgp function, with no changes in the physiological expression of this protein. Based on that, the present study aimed to evaluate the reversal of MDR phenotype through modulation of Pgp efflux pump activity in leukemia multidrug-resistant cells, using a low dose of cyclosporine A (CsA). We showed that modulation of Pgp activity by using CsA did not induce cytotoxic effects in leukemia cells, independently of Pgp expression. However, during the modulation condition, we could observe that vincristine-induced apoptosis was significant in resistant cells, which was also coupled with decreasing expression of the inhibitor of apoptosis protein XIAP. In summary, our data suggest that CsA is able to reversing MDR phenotype in vitro, inducing sensibility in multidrug-resistant cells with no alterations in Pgp expression. These findings contribute to our knowledge for the circumvention of MDR in cancer cells and could be helpful for new treatment approaches.