title: Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside.
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.
authors.affiliation: Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Gasthuisberg, O&N, Herestraat 49 bus 902, B-3000, Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Beckers
authors.forename: Sophie
authors.initials: S
authors.lastname: Organe
authors.forename: Leen
authors.initials: L
authors.lastname: Timmermans
authors.forename: Frank
authors.initials: F
authors.lastname: Vanderhoydonc
authors.forename: Ludo
authors.initials: L
authors.lastname: Deboel
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.forename: Koen
authors.initials: K
authors.lastname: Brusselmans
authors.forename: Guido
authors.initials: G
authors.lastname: Verhoeven
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
mesh_terms: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D008727:Methotrexate / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009709:Nucleotide Deaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011687:Purines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D034622:RNA Interference; D012263:Ribonucleosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D012265:Ribonucleotides / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D008055:Lipids; D009097:Multienzyme Complexes; D011687:Purines; D012263:Ribonucleosides; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D000255:Adenosine Triphosphate; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D009709:Nucleotide Deaminases; C021436:IMP cyclohydrolase; C031143:AICA ribonucleotide; C030985:purine; D008727:Methotrexate