Patterns of the Expression of Cyclin Genes in Bortezomib-Sensitive and Resistant Cells of Multiple Myeloma.

Multiple myeloma (MM) is a blood cancer defined by the accumulation of abnormal plasma cells in the bone marrow. Bortezomib is still one of the most effectual anti-cancer drugs used for the treatment of MM. However, drug-resistance prevents the efficacy of chemotherapy. One of the mechanisms causing drug-resistance is changes in regulatory factors involved cell-cycle-checkpoints. In this study, the expression levels of cyclin-D1, cyclin-D2, cyclin-A1, cyclin-E1 and cyclin-B1 genes in bortezomib-sensitive (KMS-28)/resistant (KMS-20) multiple myeloma cell lines and their effects on resistance were investigated. MTT-assay was performed to determine bortezomib cytotoxicity in both cell lines. RNA isolation and cDNA synthesis were done from bortezomib treated cells. Expressions of the genes were analyzed by Real-Time-qPCR. The results of the study showed that cyclin-A1 was not expressed in bortezomib-sensitive cells, but overexpressed in bortezomib-resistant cells. This study was the first to demonstrate a direct role of cyclin-A1 at the development of bortezomib-resistance in MM. It was observed that cyclin-D1 expression increased in KMS-28 and decreased in KMS-20 cells. The results of the study suggest that suppression of cyclin-D1 in KMS-20 cells prevents apoptosis formation and therefore causes resistance. However, we found no evidence of an association of the cyclin-D2, cyclin-E1 and cyclin-B1 genes with the development of resistance. Consequently, the findings of the study will enable us to better understand MM disease at the molecular level and to develop new treatment strategies to prevent bortezomib resistance. [ABSTRACT FROM AUTHOR]