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Amongst cancers with poor prognosis those originating from breast commonly metastasise to the skeleton for the high affinity of breast cancer cells to bone. A(3) adenosine receptor (A(3)AR) agonists were found to be potent anti-tumour agents even if their effect on bone-residing breast cancer has not yet been investigated. An animal model of surgery-induced metastasis was used to mimic the human condition in an attempt to develop a novel effective treatment strategy. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed cancer-associated osteolytic lesions and structural damage that were monitored by microcomputed tomography imaging and histological analysis. To address the involvement of A(3)ARs in tumour-related signalling pathway, A(3)AR expression and functional role were analysed in MRMT-1 cells. The effect of chronic treatment with an A(3)AR agonist, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-uronamide (Cl-IB-MECA) in comparison with cisplatin, was evaluated on rat tumour growth and bone cancer pain. A(3)ARs were expressed in MRMT-1 cells and their activation reduced NF-kB, increased p53 expression and apoptosis, inhibited tumour cell proliferation and migration. In vivo Cl-IB-MECA administration, started on day 1 after tumour cell injection, produced a significant reduction in tumour growth and cancer pain. Cl-IB-MECA treatment, performed on days 5 and 10 after the tumour cell inoculation, revealed the capability of A(3)AR stimulation to partially reduce tumour progression. Our findings highlighted the effectiveness of A(3)AR stimulation in the inhibition of breast tumour-derived bone metastasis growth strongly suggesting that targeting A(3)ARs may have promising therapeutic value in the treatment of bone-residing breast cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A(2A) adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A(2A)ARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A(2A)AR stimulation in a rat model of arthritis. We investigated A(2A)AR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A(2A)ARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A(2A)AR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A(2A)AR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A(2A)AR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A(2A)AR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A(2A)AR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A(2A)ARs in lymphocytes from RA patients. The effectiveness of A(2A)AR stimulation in a rat model of arthritis supported the role of A(2A)AR agonists as potential pharmacological treatment for RA.