Effects of synthetic A3 adenosine receptor agonists on cell proliferation and viability are receptor independent at micromolar concentrations
Language English Country Spain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Adenosine analogs & derivatives pharmacology MeSH
- Adenosine A3 Receptor Agonists pharmacology MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Cytotoxins pharmacology MeSH
- Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- Mitogen-Activated Protein Kinase 1 antagonists & inhibitors genetics metabolism MeSH
- Mitogen-Activated Protein Kinase 3 antagonists & inhibitors genetics metabolism MeSH
- Cell Proliferation drug effects MeSH
- Proto-Oncogene Proteins c-akt genetics metabolism MeSH
- Receptor, Adenosine A3 genetics metabolism MeSH
- Gene Expression Regulation MeSH
- Signal Transduction drug effects MeSH
- Transfection MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide MeSH Browser
- Adenosine MeSH
- Adenosine A3 Receptor Agonists MeSH
- Cytotoxins MeSH
- MAPK1 protein, human MeSH Browser
- Mitogen-Activated Protein Kinase 1 MeSH
- Mitogen-Activated Protein Kinase 3 MeSH
- N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine MeSH Browser
- Proto-Oncogene Proteins c-akt MeSH
- Receptor, Adenosine A3 MeSH
The question as to whether A3 adenosine receptor (A3AR) agonists, N (6)-(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA) and 2-chloro-N (6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), could exert cytotoxic effects at high concentrations with or without the involvement of A3AR has been a controversial issue for a long time. The initial findings suggesting that A3AR plays a crucial role in the induction of cell death upon treatment with micromolar concentrations of IB-MECA or Cl-IB-MECA were revised, however, the direct and unequivocal evidence is still missing. Therefore, the sensitivity of Chinese hamster ovary (CHO) cells transfected with human recombinant A3AR (A3-CHO) and their counter partner wild-type CHO cells, which do not express any of adenosine receptors, to micromolar concentrations of IB-MECA and Cl-IB-MECA was studied. We observed that IB-MECA and Cl-IB-MECA exhibited a strong inhibitory effect on cell proliferation due to the blockage of cell cycle progression at G1/S and G2/M transitions in both A3-CHO and CHO cells. Further analysis revealed that IB-MECA and Cl-IB-MECA attenuated the Erk1/2 signalling irrespectively to A3AR expression. In addition, Cl-IB-MECA induced massive cell death mainly with hallmarks of a necrosis in both cell lines. In contrast, IB-MECA affected cell viability only slightly independently of A3AR expression. IB-MECA induced cell death that exhibited apoptotic hallmarks. In general, the sensitivity of A3-CHO cells to micromolar concentrations of IB-MECA and Cl-IB-MECA was somewhat, but not significantly, higher than that observed in the CHO cells. These results strongly suggest that IB-MECA and Cl-IB-MECA exert cytotoxic effects at micromolar concentrations independently of A3AR expression.
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