title: The cytotoxicity of a Grb2-SH3 inhibitor in Bcr-Abl positive K562 cells.
abstract: Chronic myelogenous leukemia (CML) is characterized by the presence of Bcr-Abl oncoprotein. Gleevec has been designed to treat many CML patients by specifically targeting Bcr-Abl, but resistance to it is already apparent in many cases. In CML cells, Bcr-Abl activates several signaling pathways, including the Ras-dependent pathway, in which growth factor receptor binding 2 (Grb2) acts as an adaptor protein. A specific Grb2-SH3 inhibitor (denoted as peptidimer-c) that disrupts Grb2-Sos complex was designed and synthesized in our laboratory. In this study, we investigated the effect and the molecular mechanism of this inhibitor. Peptidimer-c was shown to bind to Grb2 in K562 cells, a cell line over-expressing Bcr-Abl oncoprotein. It caused cytotoxicity in the cells, and inhibited their ability of colony formation in the semi-solid medium. It was shown to induce apoptosis of K562 cells in a dose-dependent mode, the apoptotic effect of peptidimer-c being associated with caspase-3 activation. The effect of peptidimer-c on growth inhibition was also shown to be accompanied by S-phase arrest of cell cycle mediated by down-regulation of cyclin A and Cdk2, as well as phospho-Cdk2. The above results indicated that peptidimer-c may be another potential therapeutic agent for CML, which can induce S-phase arrest in the Bcr-Abl positive K562.
authors.affiliation: Université Paris Descartes, Laboratoire de Pharmacochime Moléculaire et Cellulaire, INSERM U648, 45 Rue des Saints Peres, Paris 75006, France.
authors.forename: Yun-Bin
authors.initials: YB
authors.lastname: Ye
authors.forename: Jian-Yin
authors.initials: JY
authors.lastname: Lin
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Hui-Jing
authors.initials: HJ
authors.lastname: Chen
authors.forename: Jie-Yu
authors.initials: JY
authors.lastname: Li
authors.forename: Wang-Qing
authors.initials: WQ
authors.lastname: Liu
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002352:Carrier Proteins / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013997:Time Factors; D018909:src Homology Domains / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D019925:Cyclin A; D051380:GRB2 Adaptor Protein; D010446:Peptide Fragments; D010455:Peptides; D010879:Piperazines; D011743:Pyrimidines; C529439:peptidimer-c; D000068877:Imatinib Mesylate; C414409:penetratin; D016044:Fusion Proteins, bcr-abl; D053148:Caspase 3