title: 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.affiliation: Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, UK. huw.lewis.1991@pem.cam.ac.uk
authors.forename: Huw D
authors.initials: HD
authors.lastname: Lewis
authors.forename: Matthew
authors.initials: M
authors.lastname: Leveridge
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strack
authors.forename: Christine D
authors.initials: CD
authors.lastname: Haldon
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'neil
authors.forename: Hellen
authors.initials: H
authors.lastname: Kim
authors.forename: Andrew
authors.initials: A
authors.lastname: Madin
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Hannam
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Nancy
authors.initials: N
authors.lastname: Kohl
authors.forename: Giulio
authors.initials: G
authors.lastname: Draetta
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kerby
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; C523799:MRK 003; D051880:Receptors, Notch; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases