Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling.
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.
Lewis
Huw D
HD
Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, UK. huw.lewis.1991@pem.cam.ac.uk
Leveridge
Matthew
M
Strack
Peter R
PR
Haldon
Christine D
CD
O'neil
Jennifer
J
Kim
Hellen
H
Madin
Andrew
A
Hannam
Joanne C
JC
Look
A Thomas
AT
Kohl
Nancy
N
Draetta
Giulio
G
Harrison
Timothy
T
Kerby
Julie A
JA
Shearman
Mark S
MS
Beher
Dirk
D
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
D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; C523799:MRK 003; D051880:Receptors, Notch; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases