Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling.

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.

• Authors: Huw D Lewis, Matthew Leveridge, Peter R Strack, Christine D Haldon, Jennifer O'neil, Hellen Kim, Andrew Madin, Joanne C Hannam, A Thomas Look, Nancy Kohl, Giulio Draetta, Timothy Harrison, Julie A Kerby, Mark S Shearman, Dirk Beher
• Journal: Chemistry & biology (Chem Biol) Vol. 14 Issue 2 Pg. 209-19 (Feb 2007) ISSN: 1074-5521 [Print] United States
• PMID: 17317574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, enzymology, metabolism, pathology)
• Receptors, Notch (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Thiadiazoles (pharmacology)