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.

• 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