Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia

Cancer Lett. 2017 Oct 1;405:73-78. doi: 10.1016/j.canlet.2017.07.019. Epub 2017 Jul 26.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease of the blood affecting children, adolescents and adults. Although current treatment protocols for T-ALL have improved overall survival, a portion of T-ALL patients still experiences treatment failure. Thus, the development of novel therapies is needed. In this study, we used several patient-derived T-ALL cell lines to screen for an effective drug for T-ALL. Using a panel of 378 inhibitors against different kinases, we identified the CDK inhibitor dinaciclib as a potential drug for T-ALL. Dinaciclib treatment significantly reduced cell viability and completely blocked colony formation. Furthermore, cells treated with dinaciclib showed decreased expression of several pro-survival proteins including survivin, cyclin T1 and c-MYC. Dinaciclib treatment also increased accumulation of cells in G2/M phase and significantly induced apoptosis. Finally, dinaciclib extended survival of mice in a T-ALL cell xenograft model. Collectively, these data suggest that the CDK inhibitor dinaciclib is an active drug for T-ALL in the preclinical settings.

Keywords: Apoptosis; CDK inhibitor; Cell cycle; T-ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apoptosis / drug effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinases / metabolism
  • Disease Models, Animal
  • Humans
  • Mice
  • Molecular Targeted Therapy / methods*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridinium Compounds / pharmacology*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Protein Kinase Inhibitors
  • Pyridinium Compounds
  • dinaciclib
  • Cyclin-Dependent Kinases