کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2515253 1118509 2007 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2′-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2′-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB
چکیده انگلیسی

EHEB leukemic cells, which are derived from a patient suffering B-cell chronic lymphocytic leukemia (B-CLL), display intermediate sensitivity to the purine analogue 2-chloro-2′-deoxyadenosine (CdA). Because the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway can rescue cancer cells from apoptotic signals, we investigated MAPK/ERK signaling in EHEB cells in response to CdA. We observed that CdA, at concentrations around its IC50, dose- and time-dependently increased the phosphorylation state of ERK 1/2 (p-ERK), indicating an activation of the MAPK/ERK pathway. This activation required CdA metabolism and de novo protein synthesis, and was independent on caspase activation. Interruption of ERK signaling, using the specific MEK inhibitors U-0126 and PD-98059, significantly enhanced CdA cytotoxicity, evaluated by the MTT assay. Drug interaction analysis showed synergism in the majority of combinations between CdA and MEK inhibitors tested. MEK inhibitors also dramatically increased apoptosis induced by CdA alone, evaluated by caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Collectivelly, these observations show that ERK 1/2 activation elicited by CdA serves as a cytoprotective function and suggest that inhibitors of this pathway could be combined with CdA in the treatment of selected hematological malignancies.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 73, Issue 3, 1 February 2007, Pages 351–358
نویسندگان
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