title: Bortezomib suppresses the growth of leukemia cells with Notch1 overexpression in vivo and in vitro.
abstract: Bortezomib has been widely used in the treatment of various cancers; however, its exact mechanisms of action are not fully understood, particularly in acute T lymphoblast leukemia (T-ALL). Here, we visualize the anti-leukemia effect of bortezomib in both human T-ALL cell line and animal models. In vitro study, a human T-ALL cell line bearing Notch1 mutations, MOLT-4, was treated with bortezomib. At clinically achievable concentrations, bortezomib inhibited cell growth by inducing G1 phase arrest and apoptosis with a dose-dependent manner. A murine tumor xenograft model was achieved by subcutaneous injection of MOLT-4 cells for in vivo study. Administration of bortezomib significantly reduced tumor mass volume when compared with controls. Of note, bortezomib inhibited growth of leukemia cells in a Notch1-induced murine T-ALL model, and the life span of leukemia-bearing mice was markedly increased. Further studies revealed that bortezomib led to inhibited expression of Notch1 target genes. Taken together, our results demonstrate that bortezomib shows significant anti-leukemia effect in T-ALL bearing Notch1 mutations in vitro and in vivo. The present study provides evidence that bortezomib might be a candidate therapeutic reagent in the treatment of T-ALL.
authors.affiliation: Department of Hematology, Institute of Hematology, PLA, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chongmei
authors.initials: C
authors.lastname: Huang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.forename: Libing
authors.initials: L
authors.lastname: Wang
authors.forename: Shuqing
authors.initials: S
authors.lastname: Lü
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.forename: Xianmin
authors.initials: X
authors.lastname: Song
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C497761:NOTCH1 protein, human; D011719:Pyrazines; D051881:Receptor, Notch1; D000069286:Bortezomib