CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Abstract

The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (cdK) family, cdK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of cdK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells.In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of cdK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.

CDK9 inhibitors in multiple myeloma: a review of progress and perspectives

“…Hence, the combination of both drugs changes the intracellular balance to favor apoptosis. P276-00 was tested together with Bortezomib in myeloma cells and showed marked synergism [ 34 ], which coincides with the results of SLM-6 [ 86 ] and Dinaciclib [ 87 ]. The combination of Doxorubicin, Bortezomib and either P276-00 [ 34 ] or Seliciclib [ 59 ] were also deemed effective.…”

“…A synergy between CPI-203, a novel bromodomain inhibitor, and either Bortezomib or Lenalidomide was also observed [ 86 , 87 ]. Lenalidomide contributes to overcoming resistance to Bortezomib via inhibition of IRF4, which leads to MYC downregulation [ 93 ].…”

The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib

“…Single-point mutations and modification of gene expression in neoplastic cells refractory to PI have been reported in previous studies [11,[13][14][15][16][17]. Several genes associated with bortezomib resistance have been identified in MM cells, including POMP, XBP1, PSMB5, MARCKS, ABCB1, CXCR4, MAF, TXN, TJP1, RPL5, CDK5 and CYP1A1 [18][19][20][21][22][23][24][25]; however, these genes have been examined individually, and usually only using commercially-available MM cell lines. The present study comprehensively examines the mRNA expression of nine previously-described genes that may affect resistance in patients with a clinicallydetected loss of response to PI treatment: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN and XBP1.…”

The Value of Serum MicroRNA Expression Signature in Predicting Refractoriness to Bortezomib-Based Therapy in Multiple Myeloma Patients

“…Our findings demonstrated that serum expression of several miRNAs differs between patients who are refractory to bortezomib and those who are sensitive. However, it is important to examine the roles of these miRNAs in the regulation of recently-identified genes associated with bortezomib resistance, such as PSMB5 , CDK5 and CYP1A1 , in MM cells [ 81 , 82 , 83 ]. It has been reported previously that miRNAs can modulate the expression of genes responsible for bortezomib refractoriness in MM cells; for example, CDK5 expression may be related to miR-27a-5p activity [ 84 ].…”