کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2515208 | 1118506 | 2008 | 12 صفحه PDF | دانلود رایگان |
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.
Journal: Biochemical Pharmacology - Volume 75, Issue 11, 1 June 2008, Pages 2080–2091