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.

Salinomycin enhances doxorubicin-induced cytotoxicity in multidrug resistant MCF-7/MDR human breast cancer cells via decreased efflux of doxorubicin

“…Another important feature of salinomycin is that it facilitates bidirectional ion flux through the lipid barrier of membranes, acting as channel blockers to inhibit cell proliferation (29). A similar competitive mechanism has been observed in the reversal of MDR by P-gp inhibitors, including verapamil and cyclosporine A (30,31). In the present study, an efflux was examined using RT-qPCR and western blot analysis, to determine whether this accumulation effect was directly associated with the gene and protein expression of MDR1 and MRP.…”

HG-829 Is a Potent Noncompetitive Inhibitor of the ATP-Binding Cassette Multidrug Resistance Transporter ABCB1

“…Cyclosporin A displayed remarkable drug-dependent variability. There was no enhancement of paclitaxel, vincristine, or etoposide cytotoxicity in resistant cell lines; however, vinblastine resistance was effectively reversed in H460/VBL cells, a result that was similar to data reported by de Souza and colleagues (23). Our investigations show that the novel substituted quinoline, HG-829, is a potent and selective inhibitor of ABCB1 -mediated MDR, with comparable activity in reversing resistance in both drug-selected and ABCB1 -transfected cells that extends to all Pgp substrates investigated, including daunorubicin, doxorubicin, paclitaxel, vinblastine, vincristine, and etoposide.…”

Microparticles induce multifactorial resistance through oncogenic pathways independently of cancer cell type

“…These data are supported by our previous study, which showed that XIAP contributed to cisplatin and vincristine drug resistance in CML cells with inhibited Pgp activity. 33 However, MCF7 cells showed paclitaxel-induced apoptotic evasion after co-culturing. Because no IAP protein expression changes were observed in MCF7 cells, other than a slight increase in XIAP levels, we assume that paclitaxel resistance in MCF7 cells results from Pgp expression and activity.…”