Apoptosis in T Cell Acute Lymphoblastic Leukemia Cells After Cell Cycle Arrest Induced by Pharmacological Inhibition of Notch Signaling

Chem Biol. 2007 Feb;14(2):209-19. doi: 10.1016/j.chembiol.2006.12.010.

Abstract

In this report, inhibitors of the gamma-secretase enzyme have been exploited to characterize the antiproliferative relationship between target inhibition and cellular responses in Notch-dependent human T cell acute lymphoblastic leukemia (T-ALL) cell lines. Inhibition of gamma-secretase led to decreased Notch signaling, measured by endogenous NOTCH intracellular domain (NICD) formation, and was associated with decreased cell viability. Flow cytometry revealed that decreased cell viability resulted from a G(0)/G(1) cell cycle block, which correlated strongly to the induction of apoptosis. These effects associated with inhibitor treatment were rescued by exogenous expression of NICD and were not mirrored when a markedly less active enantiomer was used, demonstrating the gamma-secretase dependency and specificity of these responses. Together, these data strengthen the rationale for using gamma-secretase inhibitors therapeutically and suggest that programmed cell death may contribute to reduction of tumor burden in the clinic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclic S-Oxides / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / drug therapy*
  • Leukemia-Lymphoma, Adult T-Cell / enzymology
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / pathology*
  • Receptors, Notch / antagonists & inhibitors*
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • Thiadiazoles / pharmacology

Substances

  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • MRK 003
  • Receptors, Notch
  • Thiadiazoles
  • Amyloid Precursor Protein Secretases