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crm1 br Conflict of interest br Acknowledgements
Conflict of interest
Acknowledgements
The authors would like to thank Mrs. Amparo Pacheco from CMPL, PUC, for her technical and secretarial assistance. This work was supported by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1150344, 1050377, 11150083), and the Direccioń de Investigación (2015-0032-I), Universidad San Sebastián, Chile. R. Salsoso holds the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)–-PhD (Chile) and Faculty of Medicine, Pontificia Universidad Católica de Chile–-PhD (Chile) fellowships. B. Fuenzalida hold the Faculty of Medicine, Pontificia Universidad Católica de Chile–-PhD (Chile) fellowships.
Introduction
Cancer is a complex disease caused by alterations in intrinsic and extrinsic cell processes [1]. During them, several genes coding for G-protein coupled receptors (GPCR) are upregulated, and they activate the cell death pathway to stop cancer proliferation. Adenosine receptors (ARs), one member of the GPCR family, are highly expressed in some cancer cells and tissues [2]. Moreover, these receptors play crucial role in vasculature, immune-escaping, and growth of tumour masses [3]. The AR family is constituted of four receptor subtypes, named A1, A2A, A2B, and A3, on the crm1 of difference in gene sequences and functions [4]. Recently, it has been identified that A3AR expression is greater in some tumour cells than in normal cells [[5], [6], [7]]. A3AR was also found to be over-expressed in various tumour tissues derived from patients with pancreatic, hepatocellular, and colon carcinoma [8]. Therefore, A3AR was considered as a tumour cell marker and this receptor-signalling pathway was used as a target to reduce the cancer proliferation [9]. Stimulation of A3AR induces different signal transduction pathways, which depend on cell type. This could explain the different responses obtained by this receptor stimulation. Activation of A3AR inhibits the adenylyl cyclase (AC) activity and cAMP production and lowers the PKA level [10]. Furthermore, in a cell type specific fashion, A3AR activation could lead to the formation of phosphatydil inositides, which phosphorylates the kinase PKB/Akt inducing its activation [11,12] The PKB/Akt may modulate caspases level, the expression of antiapoptotic genes, and the level of GSK-3β central protein of the Wnt signalling pathway [10]. Adenosine (Ado) inhibits in vitro tumour cell growth and stimulates bone marrow cell proliferation through the activation of A3AR [11]. It has been reported that some A3AR agonists such as N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide [IB-MECA] and 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide [Cl-IB-MECA], inhibit cancer cell proliferation in in vitro and in vivo tumour models [13,14]. Hence, Cl-IB-MECA, at nanomolar concentrations, inhibited tumour cell growth through a cytostatic pathway with an increased number of cells in the G0/G1 phase of the cell cycle and decreased the telomeric signal. Furthermore, oral administration of Cl-IB-MECA suppressed the development of melanoma lung metastases in murine model of melanoma cancer, and a synergistic anti-tumour effect was achieved when it was administered with cyclophosphamide [15]. IB-MECA was shown to deregulate the Wnt signalling pathway in some cancer cells through the inhibition of AC, and the effectors PKA and PKB. The effect was reversed by MRS-1523, a specific A3AR antagonist, demonstrating that the effect is due to the activation of this receptor [16].
We have recently reported that novel analogues of the Cl-IB-MECA are associated with higher potency and selectivity than Cl-IB-MECA. In this study, we tested the effect of a set of known and novel derivatives of adenosine in multiple cancer cell lines. In vitro studies showed that novel agonist of A3 receptor and Cl-IB-MECA inhibits the cell growth of human prostate, colon and hepatocyte carcinomas. This detailed investigation of agonist activity suggests novel agonists application as an anti-cancer agent for the treatment of multiple cancers tested.