Induction of apoptosis by A3 adenosine receptor agonist N-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide in human leukaemia cells: a possible involvement of intracellular mechanism
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
20121715
DOI
10.1111/j.1748-1716.2010.02087.x
PII: APS2087
Knihovny.cz E-zdroje
- MeSH
- adenosin analogy a deriváty chemie metabolismus MeSH
- adenosintrifosfatasy metabolismus MeSH
- agonisté adenosinového receptoru A3 * MeSH
- apoptóza fyziologie MeSH
- blokátory kalciových kanálů farmakologie MeSH
- buňky K562 účinky léků metabolismus MeSH
- HL-60 buňky účinky léků metabolismus MeSH
- lidé MeSH
- mnohočetná léková rezistence fyziologie MeSH
- P-glykoprotein antagonisté a inhibitory genetika metabolismus MeSH
- signální transdukce fyziologie MeSH
- verapamil farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenosin MeSH
- adenosintrifosfatasy MeSH
- agonisté adenosinového receptoru A3 * MeSH
- blokátory kalciových kanálů MeSH
- N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine MeSH Prohlížeč
- P-glykoprotein MeSH
- verapamil MeSH
AIM: The sensitivity of cancer cells which exhibit multi-drug resistance phenotype to A3 adenosine receptor (A3AR) agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (IB-MECA) was studied. METHODS: To establish direct relationship between P-glycoprotein (P-gp, ABCB1 and MDR1) expression and IB-MECA induced cell death, a straightforward method for precise estimation of intracellular level of this A3AR agonist was developed. RESULTS: We subjected three human leukaemia cell lines HL-60, K562 and K562/HHT to treatment with micromolar concentrations of IB-MECA. Although all cell lines used expressed A3AR, there was a large difference in their sensitivity to IB-MECA. While HL-60 and K562 cells were almost equally sensitive, the K562/HHT cells, which exhibit a multi-drug resistance phenotype because of overexpression of P-gp, were significantly more resistant. We found that the intracellular level of IB-MECA in K562/HHT cells was approx. 10 times lower than those in HL-60 or K562 cells. Inhibitors of P-gp, including cyclosporine A (CsA) and verapamil (Vpa), increased the intracellular level of IB-MECA and reversed the resistance of K562/HHT cells to this drug. Accordingly, shRNA-mediated down-regulation of P-gp significantly increased the intracellular level of IB-MECA in K562/HHT cells which simultaneously exhibited reduced resistance to this A3AR agonist. In addition, an in vitro enzyme-based assay provided evidence that IB-MECA might serve as a substrate for P-gp. CONCLUSION: Our results suggest that P-gp overexpression prevents cells from IB-MECA induced apoptosis despite the A3AR expression. Pro-apoptotic effect of IB-MECA seemed to strongly depend on its intracellular accumulation rather than on its interaction with A3AR.
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