Investigation of the usability of HSP27 inhibitor's brivudin combined with bortezomib in multiple myeloma treatment

Multiple myeloma (MM) is a hematological cancer characterized by the accumulation of malignant plasma cells responsible for the production of nonfunctional monoclonal immunoglobulin in the bone marrow. HSP27, a small member of the heat shock protein family, has shown to play a role in both the pathogenesis of MM and the development of resistance to therapy. Although great progress has been made in the myeloma treatment especially with proteasome inhibitors such as bortezomib, MM cannot be fully cured in clinical practice. The aim of this study is to investigate the usability of biruvidin, an antiviral drug, in the treatment of myeloma combined with bortezomib. For this purpose, we detected the cytotoxicity of brivudine (BRVD) and bortezomib (BZM) alone or in combination in U266 and RPMI-8226 human myeloma cell lines using the MTT test. We calculated the IC50 doses at 48 hours for both cell lines of BZM and BRVD. We determined the cytotoxicity in U266 and RPMI-8226 cell lines by keeping the BZM constant at the IC50 dose and changing the BRVD concentration. We performed combination index (CI) analysis to evaluate the BZM-BRVD interaction. We also investigated the effect of BRVD and BZM application on HSP27 gene expression in U266 and RPMI-8226 cell lines using real time RT-PCR method. As a result, we found the IC50 dose of BRVD at 48 hours to be 24.39 M and 18.83 M, respectively. We found the IC50 value of BZM as 13.75 nM and 11.22 nM for 48 hours in U266 and RPMI-8226 cell lines, respectively. When the IC50 dose of BZM and the 3.75, 7.5, 15 and 30 M doses of BRVD are combined, the combination of BZM + 3.75 M BRVD has an additive effect (CI=1) on both cell lines, while all other BRVD concentrations with BZM caused an dose-dependent increased synergistic effect (CI<1). In addition, we showed that BRVD caused a significant decrease in HSP27 gene expression level in both cell lines compared to the control (p<0.05). Interestingly, we found that BZM caused a significant decrease in HSP27 gene expression level in both cell lines compared to the control (p<0.05). As a result, we suggested that the combination of BRVD-BZM can be used in the treatment of MM and suppression of the HSP27 gene expression level may play a role in the effectiveness of the treatment