Downregulation of Notch signaling by gamma-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines.
Activation of Notch1 signaling plays an important role in the pathogenesis of precursor T-cell lymphoblastic leukemia (T-ALL). The Notch1 receptor is cleaved and activated via the gamma-secretase complex. Downregulation of Notch1 signaling by gamma-secretase inhibitors (GSIs) thus represents a potential novel therapeutic approach. In this study, we analyzed the response of four T-ALL cell lines to compound E, a potent gamma-secretase inhibitor, and to the combination of compound E with vincristine, daunorubicin, L-asparaginase (L-ASP), and dexamethasone (DEX). We identified two distinct types of responses: In type 1 cell lines, represented by TALL1 and HSB2, GSI-induced apoptosis followed cell cycle arrest and enhanced the induction of apoptosis caused by DEX and L-ASP. In type 2 cell lines, represented by CEM and Jurkat J6, GSI caused neither cell cycle block nor cell death. Notably, the combination of GSI with chemotherapy-induced resistance by decreasing apoptosis. In type 2 cells, GSI induced the upregulation of Bcl-xl mRNA and protein, which was thus identified as a candidate mechanism for the inhibition of apoptosis. In conclusion, the data presented here caution against clinical use of a combination treatment of GSI and chemotherapy in T-ALL.
Liu
Shuangyou
S
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
Breit
Stephen
S
Danckwardt
Sven
S
Muckenthaler
Martina U
MU
Kulozik
Andreas E
AE
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001215:Asparaginase / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014750:Vincristine / Q000494:pharmacology
C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014750:Vincristine; D003907:Dexamethasone; D053829:Amyloid Precursor Protein Secretases; D001215:Asparaginase; D003630:Daunorubicin