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 ribosideinduced 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. [Mol Cancer Ther 2006;5(9):2211 -7]

How Metabolism Generates Signals during Innate Immunity and Inflammation

“…AMPK therefore promotes oxidative metabolism, which is associated with an anti-inflammatory state, rather than the glycolytic state associated with inflammation or tumor progression. Several anti-inflammatory drugs such as salicylate and methotrexate have been shown to activate AMPK (39,40). Yuan et al (41) demonstrated that the treatment of obese mice with salicylate results in a significant decrease in blood glucose levels, whereas clinical trials with salsalate, a non-acetylated prodrug of salicylate, showed a reduction in blood glucose levels in patients with T2D (42).…”

Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells

“…Because of the fact that AICAR has been shown to inhibit AMP deaminase, leading to the accumulation and subsequent release of adenosine into the extracellular space [25][26][27], it was essential to determine whether the anti-inflammatory effects of AICAR were attributed to AMPK activation or enhanced adenosine levels. Adenosine plays a major role in the control of renal function by regulating processes such as renal blood flow, glomerular filtration by vasoconstriction of the afferent arteriole, renin secretion and tubuloglomerular feedback, but it can also block inflammation [28,29].…”

Low-Dose Methotrexate Results in the Selective Accumulation of Aminoimidazole Carboxamide Ribotide in an Erythroblastoid Cell Line

“…Elevated levels of extracellular adenosine, through adenosine receptor activation, result in a reduction in inflammation and may depend on MTX polyglutamate formation (Baggott et al, 1986;Cronstein et al, 1993;Urakawa et al, 2000;Dolezalova et al, 2005;You et al, 2013). Selective toxicity toward T cells and activation of AMP-activated protein kinase by ZMP has also been proposed as mechanisms of activity of MTX in autoimmune disorders (Taisun and Baggott, 1994;Genestier et al, 1998;Fairbanks et al, 1999;Johnston et al, 2005;Beckers et al, 2006;Katerelos et al, 2010).…”