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      New synthetic AICAR derivatives with enhanced AMPK and ACC activation

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          Abstract

          5-Aminoimidazole-4-carboxamide riboside (AICAR) has an important role in the regulation of the cellular metabolism showing a broad spectrum of therapeutic activities against different metabolic processes. Due to these proven AICAR properties, we have designed, synthesized and tested the biological activity of two ribose-modified AICAR derivatives, named A3 and A4, in comparison to native AICAR and its 5'-phosphorylated counterpart ZMP. Our findings have shown that A3 and A4 derivatives induce the phosphorylation of 5'-AMP activated protein kinase α (AMPKα), which leads to the inhibition of acetyl-CoA carboxylase (ACC), and down-regulate the activity of the extracellular signal-regulated kinases (ERK1/2). Cytotoxicity tests demonstrated that A3 and A4 do not significantly reduce cell viability up to 24 h. Taken together our results indicate that A3 and A4 have a comparable activity to AICAR and ZMP at 0.5 and 1 mM suggesting their potential use in future pharmacological strategies relating to metabolic diseases.

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          5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase.

          Inderjit Singh, Shailendra Giri, Avtar Singh … (2005)
          5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) is widely used as an AMP-kinase activator, which regulates energy homeostasis and response to metabolic stress. Here, we investigated the effect of AICAR, an AMPK activator, on proliferation of various cancer cells and observed that proliferation of all the examined cell lines was significantly inhibited by AICAR treatment due to arrest in S-phase accompanied with increased expression of p21, p27, and p53 proteins and inhibition of PI3K-Akt pathway. Inhibition in in vitro growth of cancer cells was mirrored in vivo with increased expression of p21, p27, and p53 and attenuation of Akt phosphorylation. Anti-proliferative effect of AICAR is mediated through activated AMP-activated protein kinase (AMPK) as iodotubericidin and dominant-negative AMPK expression vector reversed the AICAR-mediated growth arrest. Moreover, constitutive active AMPK arrested the cells in S-phase by inducing the expression of p21, p27, and p53 proteins and inhibiting Akt phosphorylation, suggesting the involvement of AMPK. AICAR inhibited proliferation in both LKB and LKB knock-out mouse embryo fibroblasts to similar extent and arrested cells at S-phase when transfected with dominant negative expression vector of LKB. Altogether, these results indicate that AICAR can be utilized as a therapeutic drug to inhibit cancer, and AMPK can be a potential target for treatment of various cancers independent of the functional tumor suppressor gene, LKB.
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            AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms.

            Xiaoqin Xiang, Asish K Saha, Rong Wen … (2004)
            Prostate cancer cells require high rates of de novo fatty acid synthesis and protein synthesis for their rapid growth. We report here that the growth of these cells is markedly diminished by incubation with activators of AMP-activated protein kinase (AMPK), a fuel-sensing enzyme that has been shown to diminish both of these processes in intact tissues. Inhibition of cell growth was observed when AMPK was activated by either 5-aminoimidazole-4-carboxamide riboside (AICAR) or the thiazolidinedione rosiglitazone. Thus, a 90% inhibition of the growth of androgen-independent (DU145, PC3) and androgen-sensitive (LNCaP) cells was achieved after 4 days of exposure to one or both of these agents. Where studied, this was associated with a decrease in the concentration of malonyl CoA, an intermediate of de novo fatty acid synthesis, and an increase in expression of the cell cycle inhibitor p21. In addition, AICAR inhibited two key enzymes involved in protein synthesis, mTOR and p70S6K, and blocked the ability of the androgen R1881 to increase cell growth and the expression of two enzymes for de novo fatty acid synthesis, acetyl CoA carboxylase and fatty acid synthase, in the LNCaP cells. The results suggest that AMPK is a potential target for the treatment of prostate cancer.
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              Adiponectin affects lung epithelial A549 cell viability counteracting TNFα and IL-1ß toxicity through AdipoR1.

              Matteo Sofia, Ersilia Nigro, Olga Scudiero … (2013)
              Adiponectin (Acrp30) exerts protective functions on metabolic and cellular processes as energy metabolism, cell proliferation and differentiation by two widely expressed receptors, AdipoR1 and AdipoR2. To date, the biological role of Acrp30 in lung has not been completely assessed but altered levels of Acrp30 and modulated expression of both AdipoRs have been related to establishment and progression of chronic obstructive pulmonary disease (COPD) and lung cancer. Here, we investigated the effects of Acrp30 on A549, a human alveolar epithelial cell line, showing how, in a time and dose-dependent manner, it decreases cell viability and increases apoptosis through ERK1/2 and AKT. Furthermore, we examined the effects of Acrp30 on A549 cells exposed to TNFα and/or IL-1ß, two potent lung inflammatory cytokines. We showed that Acrp30, in dose- and time-dependent manner, reduces cytotoxic effects of TNFα and/or IL-1ß improving cell viability and decreasing apoptosis. In addition, Acrp30 inhibits NF-κB nuclear trans-activation and induces the expression of the anti-inflammatory IL-10 cytokine without modifying that of pro-inflammatory IL-6, IL-8, and MCP-1 molecules via ERK1/2 and AKT. Finally, specifically silencing AdipoR1 or AdipoR2, we observed that NF-κB inhibition is mainly mediated by AdipoR1. Taken together, our data provides novel evidence for a direct effect of Acrp30 on the proliferation and inflammation status of A549 cells strongly supporting the hypothesis for a protective role of Acrp30 in lung. Further studies are needed to fully elucidate the Acrp30 lung effects in vivo but our results confirm this adipokine as a promising therapeutic target in lung diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Title: Journal of Enzyme Inhibition and Medicinal Chemistry
                Abbreviated Title: Journal of Enzyme Inhibition and Medicinal Chemistry
                Publisher: Informa UK Limited
                ISSN (Print): 1475-6366
                ISSN (Electronic): 1475-6374
                Publication date Created: August 06 2015
                Publication date Created: September 02 2016
                Publication date (Electronic): October 08 2015
                Publication date (Print): September 02 2016
                Volume: 31
                Issue: 5
                Pages: 748-753
                Article
                DOI: 10.3109/14756366.2015.1063622
                PubMed ID: 26446934
                SO-VID: 29706d4f-a6da-4932-8e58-1488de184222
                Copyright © © 2016
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