The role of АВС transporters in drug resistance to bortezomib in multiple myeloma

Abstract

Background. In our work, we investigated the role of ABC transporters and the transcription factor YB-1 protein in the formation of drug resistance to the proteasome inhibitor bortezomib in multiple myeloma.Materials and methods. We used the RPMI8226 and NCI-H929 cultures and their bortezomib-resistant sublines as models.Results. Two major ABC transporter proteins, P-glycoprotein and MRP1, are not involved in the emergence of resistance to bortezomib, moreover, bortezomib contributed to decrease of these genes expression. Expression of the MVP gene was increased only in the resistant RPMI8226/btz-6 variant, but not in H929/btz-6. The localization of the YB-1 protein, a transcription factor for the MDR1, MRP1 and MVP genes, changed only in RPMI8226/btz-6 cells, as well, it became diffuse in 20 % of the cells as compared to 7 % of the cells in the RPMI8226 parent line. The only ABC transporter gene, activated in both RPMI8226/btz-6 and H929/btz-6 sublines, was BCRP. Сross-resistance to doxorubicin is also shown for these sublines.Conclusion. Thus, the activation of ABC transporters is not a key mechanism for the formation of bortezomib drug resistance. MVP protein may play certain role, and an increase in the BCRP expression explains the emergence of resistance to doxorubicin, but not to bortezomib, since the latter is not a substrate of BCRP.

Keywords

• bortezomib
• multiple myeloma
• multidrug resistance
• abc-transporter
• yb-1
• p-glycoprotein
• mrp1
• bcrp
• mvp