Pharmacological and therapeutic effects of A(3) adenosine receptor agonists

Can-Fite BioPharma Ltd, Kiryat-Matalon, 10 Bareket St, PO Box 7537, Petah-Tikva 49170, Israel.
Drug discovery today (Impact Factor: 6.69). 10/2011; 17(7-8):359-66. DOI: 10.1016/j.drudis.2011.10.007
Source: PubMed


The A(3) adenosine receptor (A(3)AR) coupled to G(i) (inhibitory regulative guanine nucleotide-binding protein) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A(3)AR as a potential therapeutic target. Highly selective A(3)AR agonists have been synthesized and molecular recognition in the binding site has been characterized. In this article, we summarize preclinical and clinical human studies that demonstrate that A(3)AR agonists induce specific anti-inflammatory and anticancer effects through a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. At present, A(3)AR agonists are being developed for the treatment of inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis.

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    • "Thus, the A 3 R agonist exhibited both anticancer effects and anti-cancer pain effects (Varani et al., 2013). A 3 Rs are upregulated in synovial tissue and circulating mononuclear cells in rheumatoid arthritis (Ochaion et al., 2009; Varani et al., 2011), and exploration of the clinical effects of A 3 R agonists for this condition has commenced (Silverman et al., 2008; Fishman et al., 2012). A further potential approach that may be effective in conditions where there are enhanced endogenous adenosine levels is to use allosteric modulators which would have selective actions at sites where elevation of adenosine levels occurs. "
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    ABSTRACT: The main focus for development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signalling and may be useful for inflammatory and neuropathic pain. A2BR agonists exhibit peripheral proinflammatory effects on immune cells, but also spinal antinociceptive effects similar to A2AR agonists. A3Rs are now demonstrated to produce antinociception in several preclinical neuropathic pain models, with mechanistic actions on glial cells, and may be useful for neuropathic pain. Endogenous adenosine levels can be augmented by inhibition of metabolism (via adenosine kinase) or increased generation (via nucleotidases), and these approaches have implications for pain. Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating efficacy of adenosine-based analgesics.
    Neuroscience 10/2015; DOI:10.1016/j.neuroscience.2015.10.031 · 3.36 Impact Factor
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    • "Two cell lines (MCF-7 and DU-145) were selected on the basis of over expression of adenosine receptors (Aghaei et al., 2012; Fishman et al., 2012). Cell lines were grown as adherent in DMEM medium supplemented with 10% fetal bovine serum, 100 mg/ml penicillin, 200 mg/ml streptomycin, 2 mM L-glutamine, and culture was maintained in a humidified atmosphere with 5% CO 2 . "
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    ABSTRACT: Delivering chemotherapeutics by nanoparticles into tumor is impeded majorly by two factors: nonspecific targeting and inefficient penetration. Targeted delivery of anti-cancer agents solely to tumor cells introduces a smart strategy because it enhances the therapeutic index compared with untargeted drugs. The present study was performed to investigate the efficiency of adenosine (ADN) to target solid lipid nanoparticles (SLN) to over expressing adenosine receptor cell lines such as human breast cancer and prostate cancer (MCF-7 and DU-145 cells), respectively. SLN were prepared by emulsification and solvent evaporation process using docetaxel (DTX) as drug and were characterized by various techniques like dynamic light scattering, differential scanning calorimeter and transmission electron microscopy. DTX loaded SLNs were surface modified with ADN, an adenosine receptors ligand using carbodiimide coupling. Conjugation was confirmed using infrared spectroscopy and quantified using phenol-sulfuric acid method. Conjugated SLN were shown to have sustained drug release as compared to unconjugated nanoparticles and drug suspension. Compared with free DTX and unconjugated SLN, ADN conjugated SLN showed significantly higher cytotoxicity of loaded DTX, as evidenced by in vitro cell experiments. The IC50 was 0.41μg/ml for native DTX, 0.30μg/ml for unconjugated SLN formulation, and 0.09μg/ml for ADN conjugated SLN formulation in MCF-7 cell lines. Whereas, in DU-145, there was 2 fold change in IC50 of ADN-SLN as compared to DTX. IC50 was found to be 0.44μg/ml for free DTX, 0.39μg/ml for unconjugated SLN and 0.22μg/ml for ADN-SLN. Annexin assay and cell cycle analysis assay further substantiated the cell cytotoxicity. Fluorescent cell uptake and competitive ligand-receptor binding assay corroborated the receptor mediated endocytosis pathway indicated role of adenosine receptors in internalization of conjugated particles. Pharmacokinetic studies of lipidic formulations depicted significant improvement in pharmacokinetic parameters than marketed formulation. ADN conjugated SLN proved to be an efficient drug delivery vehicle. Hence, ADN can be used as a potential ligand to target breast and prostate cancer. Copyright © 2015. Published by Elsevier B.V.
    International Journal of Pharmaceutics 03/2015; 486(1-2). DOI:10.1016/j.ijpharm.2015.03.065 · 3.65 Impact Factor
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    • "Our results substantially extend our previous findings exploring A 3 AR in pain (Chen et al., 2012) by identifying an endogenous analgesic A 3 AR pathway within key regions of the CNS that is distinguished by its potent efficacy and state-dependent nature, functioning to suppress only pathological pain without altering the normal pain threshold or activating reward centres in normal rats. Cardiovascular side effects are the major limitation of therapeutic approaches that enhance adenosine signalling (Fredholm et al., 2011; Zylka, 2011; Boison, 2013); however, A 3 AR agonists in clinical trials, IB-MECA and Cl-IBMECA, have no reported serious side effects (Fishman et al., 2012). Yet, while these prototypical A 3 AR agonists were anti-nociceptive in our preclinical studies (Chen et al., 2012 "
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    ABSTRACT: Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
    Brain 11/2014; 138(1). DOI:10.1093/brain/awu330 · 9.20 Impact Factor
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