Putative role of the adenosine A3 receptor in the antiproliferative action of N6-2-isopentenyladenosineReport as inadecuate

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Purinergic Signalling

, Volume 7, Issue 4, pp 453–462

First Online: 01 July 2011Received: 03 February 2011Accepted: 03 June 2011DOI: 10.1007-s11302-011-9244-9

Cite this article as: Blad, C.C., von Frijtag Drabbe Künzel, J.K., de Vries, H. et al. Purinergic Signalling 2011 7: 453. doi:10.1007-s11302-011-9244-9


We tested a panel of naturally occurring nucleosides for their affinity towards adenosine receptors. Both N-2-isopentenyladenosine IPA and racemic zeatin riboside were shown to be selective human adenosine A3 receptor hA3R ligands with affinities in the high nanomolar range Ki values of 159 and 649 nM, respectively. These values were comparable to the observed Ki value of adenosine on hA3R, which was 847 nM in the same radioligand binding assay. IPA also bound with micromolar affinity to the rat A3R. In a functional assay in Chinese hamster ovary cells transfected with hA3R, IPA and zeatin riboside inhibited forskolin-induced cAMP formation at micromolar potencies. The effect of IPA could be blocked by the A3R antagonist VUF5574. Both IPA and reference A3R agonist 2-chloro-N-3-iodobenzyladenosine-5′-N-methylcarboxamide Cl-IB-MECA have known antitumor effects. We demonstrated strong and highly similar antiproliferative effects of IPA and Cl-IB-MECA on human and rat tumor cell lines LNCaP and N1S1. Importantly, the antiproliferative effect of low concentrations of IPA on LNCaP cells could be fully blocked by the selective A3R antagonist MRS1523. At higher concentrations, IPA appeared to inhibit cell growth by an A3R-independent mechanism, as was previously reported for other A3R agonists. We used HPLC to investigate the presence of endogenous IPA in rat muscle tissue, but we could not detect the compound. In conclusion, the antiproliferative effects of the naturally occurring nucleoside IPA are at least in part mediated by the A3R.

KeywordsAdenosine A3 receptor N-2-isopentenyladenosine IPA Antitumor agent Modified nucleoside HPLC Zeatin riboside Electronic supplementary materialThe online version of this article doi:10.1007-s11302-011-9244-9 contains supplementary material, which is available to authorized users.

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Author: Clara C. Blad - Jacobien K. von Frijtag Drabbe Künzel - Henk de Vries - Thea Mulder-Krieger - Sara Bar-Yehuda - Pnina F

Source: https://link.springer.com/

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