title: GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia.
abstract: Gamma secretase inhibitors (GSIs) comprise a growing class of compounds that interfere with the membrane-bound Notch signaling protein and its downstream intra-nuclear transcriptional targets. As GSI-I (Z-LLNle-CHO) is also a derivative of a widely used proteosome inhibitor MG-132, we hypothesized that this compound might be active in precursor-B acute lymphoblastic leukemia (ALL) cell lines and patient samples. We found that GSI-I treatment of precursor-B ALL blasts induced apoptotic cell death within 18-24 h. With confirmation using RNA and protein analyses, GSI-I blocked nuclear accumulation of cleaved Notch1 and Notch2, and inhibited Notch targets Hey2 and Myc. Microarray analyses of 207 children with high-risk precursor-B ALL demonstrate that Notch pathway expression is a common feature of these neoplasms. However, microarray studies also implicated additional transcriptional targets in GSI-I-dependent cell death, including genes in the unfolded protein response, nuclear factor-κB and p53 pathways. Z-LLNle-CHO blocks both γ-secretase and proteosome activity, inducing more robust cell death in precursor-B ALL cells than either proteosome-selective or γ-secretase-selective inhibitors alone. Using Z-LLNle-CHO in a nonobese diabetes/severe combined immunodeficiency (NOD/SCID) precursor-B ALL xenograft model, we found that GSI-I alone delayed or prevented engraftment of B-lymphoblasts in 50% of the animals comprising the experimental group, suggesting that this compound is worthy of additional testing.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.forename: K
authors.initials: K
authors.lastname: Matlawska-Wasowska
authors.forename: F
authors.initials: F
authors.lastname: Girodon
authors.forename: T
authors.initials: T
authors.lastname: Mazel
authors.forename: C L
authors.initials: CL
authors.lastname: Willman
authors.forename: S
authors.initials: S
authors.lastname: Atlas
authors.forename: I-M
authors.initials: IM
authors.lastname: Chen
authors.forename: R C
authors.initials: RC
authors.lastname: Harvey
authors.forename: S P
authors.initials: SP
authors.lastname: Hunger
authors.forename: S A
authors.initials: SA
authors.lastname: Ness
authors.forename: S S
authors.initials: SS
authors.lastname: Winter
authors.forename: B S
authors.initials: BS
authors.lastname: Wilson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002648:Child; D015331:Cohort Studies; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D012306:Risk; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex