Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models

Cancers

Alessandro Natoni²  Mark R. E. Coyne²  Alan Jacobsen²  Michael D. Rainey²  Gemma O𠆛rien²  Sandra Healy²  Alessia Montagnoli¹  Jürgen Moll¹  Michael O𠆝wyer³ 

[1] Nerviano Medical Sciences S.r.l., Via Pasteur 10, Nerviano 20014, Italy; E-Mail:;Centre for Chromosome Biology, School of Natural Sciences National University of Ireland Galway, Galway, Ireland; E-Mails:;Department of Medicine, National University of Ireland Galway, Galway, Ireland

关键词: apoptosis;    BCL2-family;    DNA replication;    multiple myeloma;    kinase inhibitor;    cell cycle;   

DOI  :  10.3390/cancers5030901

来源: mdpi

【 摘 要 】

Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.