Investigation of multi̇ple drug resistance mechanism developed agai̇nst to bortezomib in multiple myeloma cancer cells

Multiple Myeloma (MM) is a hematological cancer characterized by accumulation of malignant plasma cells and bortezomib is the most effective chemotherapeutic used in treatment. However, drug resistance prevents success of chemotherapy in treatment process. One of the factors causing resistance is overexpression of multiple drug resistance genes (MDR). Therefore, in this study expression levels of MDR-1 (Pgp), MRP-1, MRP-2, MRP-3, MRP-6, MRP-7 and GSTP-1 genes in MM cell lines were investigated. IC50 values of bortezomib were determined by MTT assay in KMS20 (bortezomib resistant) and KMS28 (bortezomib sensitive) multiple myeloma cell lines. RNA was isolated from both cell lines and cDNAs were obtained. Expression levels of investigating genes were analyzed by qRT-PCR. As a result of gene expression analysis, it was found that P-gp (MDR-1) was the main responsible transporter for bortezomib resistance in MM. Bortezomib is strong probably thought to be excreted from the cell with MRP transporters by glutathione with GSTP1. This was the first time that MRP-7 expression was responsible for bortezomib resistance. In addition, MRP-1 expression appears with prolonged exposure to high bortezomib doses and in the same condition MRP-2 is partially effective in the development of bortezomib resistance. This is the first report that MRP-6 expression was not associated with bortezomib resistance. MRP-3 expression was not detected in both cell lines. According to the results of this study, genes with high expression can be prevented by using appropriate siRNAs or suppressive molecules. Through the results of this study and solving all other resistance mechanisms for multiple myeloma are be possible to develop personalized treatment forms.