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Title: Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside
Authors: Beckers, Annelies ×
Organe, Sophie
Timmermans, Leen
Vanderhoydonc, Frank
Deboel, Ludo
Derua, Rita
Waelkens, Etienne
Brusselmans, Koen
Verhoeven, Guido
Swinnen, Johan #
Issue Date: Sep-2006
Publisher: American Association for Cancer Research, Inc.
Series Title: Molecular Cancer Therapeutics vol:5 issue:9 pages:2211-2217
Abstract: Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA riboside-induced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention.
URI: 
ISSN: 1535-7163
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
Laboratory of Protein Phosphorylation and Proteomics
Laboratory of Phosphoproteomics (-)
Laboratory of Lipid Metabolism and Cancer (+)
× corresponding author
# (joint) last author

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