title: Targeting Notch1 and proteasome as an effective strategy to suppress T-cell lymphoproliferative neoplasms.
abstract: The T-cell lymphoproliferative neoplasms (T-LPN) are characterized by a poor clinical outcome. Current therapeutics are mostly non-selective and may induce harmful side effects. It has been reported that NOTCH1 activation mutations frequently associate T-LPN. Because anti-Notch1 based therapies such as γ-secretase inhibitors (GSI) are less efficient and induce considerable side effects, we hypothesized that combining low concentrations of GSI and the proteasome inhibitor bortezomib (BTZ) may provide an effective and tolerable approach to treat T-LPN. Hence, we analyzed the in vitro and in vivo effects of GSI-I and BTZ, alone or in combination, against T-LPN. GSI-I and BTZ synergistically decreased cell viability, proliferation, and colony formation, and induced apoptosis in T-LPN cell lines. Furthermore, combining GSI-I and BTZ decreased the viability of primary T-LPN cells from patients. These effects were accompanied by deregulation of Notch1, AKT, ERK, JNK, p38 MAPK, and NF-κB survival pathways. Moreover, combination treatment inhibited T-LPN tumor growth in nude mice. In all experiments, combining low concentrations of GSI-I and BTZ was superior to using a single agent. Our data support that a synergistic antitumor activity exists between GSI-I and BTZ, and provide a rationale for successful utilization of dual Notch1 and proteasome inhibition to treat T-LPN.
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.
authors: Lujun
authors: L
authors: Yang
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.
authors: Shuangfeng
authors: S
authors: Zhang
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Suraj Konnath
authors: SK
authors: George
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.
authors: Rong
authors: R
authors: Teng
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.
authors: Xuefen
authors: X
authors: You
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.
authors: Mengqi
authors: M
authors: Xu
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.
authors: Hong
authors: H
authors: Liu
authors: Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, 77030, USA.
authors: Xiaoping
authors: X
authors: Sun
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, 77030, USA.
authors: Hesham M
authors: HM
authors: Amin
authors: Department of Hematology, Affiliated Hospital of The University of Nantong, Jiangsu 226001, China.|Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Wenyu
authors: W
authors: Shi
mesh_terms: D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000069286:Bortezomib / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; D051881:Receptor, Notch1; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex
keywords: Notch1; T-cell lymphoproliferative neoplasms; bortezomib; proteasome; γ-secretase inhibitors