Multiple Myeloma (MM) is a lymphatic
neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to
chemotherapy. Drug resistance, differentiation block and increased survival of the MM
tumor cells result from high
genomic instability.
Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of
cyclin D, a regulatory
protein that governs the activation of key cell cycle regulator--
cyclin dependent kinase (CDK).
Genomic instability was reported to be affected by over expression of another CDK regulator--
cyclin E (CCNE). This occurs early in
tumorigenesis in various lymphatic
malignancies including CLL, NHL and HL. We therefore sought to investigate the role of
cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with
seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM
tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with
siRNA increased the cell sensitivity to
seliciclib. Adhesion to FN of hMMCLs was prevented by
seliciclib, eliminating adhesion-mediated drug resistance of MM cells. Combination of
seliciclib with
flavopiridol effectively reduced CCNE1 and
CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that
seliciclib may be considered as essential component of modern anti MM
drug combination therapy.