The effect of cyclosporin A (CsA) on imatinib treated Bcr-Abl positive K562 cells was studied. Similarly to other authors we found that imatinib induced apoptosis and erythroid differentiation in K562 cells. While its low concentrations induced predominantly erythroid differentiation, higher concentrations induced apoptosis. We found that CsA significantly potentiated cytotoxic effects of imatinib. A detailed analysis revealed that CsA shifted the balance between differentiation and apoptosis in favour of apoptosis. Our findings indicated that the observed effect of CsA was mediated neither through inhibition of ERK1/2 (extracellular signal-regulated kinases 1/2), nor through inhibition of p38 MAPK. We further observed that CsA might sensitise cells to apoptosis due to a changed cellular redox status as combined treatment of cells with imatinib and CsA resulted in a dramatic decrease of the ratio between reduced (GSH) and oxidised (GSSG) glutathione GSH/GSSG and in a significant suppression of thioredoxin reductase enzymatic activity. Our results indicated that K562 cells did not express detectable level of P-glycoprotein (P-gp). In addition, CsA did not affect significantly the intracellular level of imatinib. Therefore we excluded the possibility that CsA increased sensitivity of cells to imatinib by the inhibition of P-gp-mediated drug efflux or by another mechanism involving modulation of intracellular drug concentration.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• bcr-abl fúzové proteiny analýza   MeSH
• buňky K562 MeSH
• cyklosporin farmakologie   MeSH
• extracelulárním signálem regulované MAP kinasy antagonisté a inhibitory   MeSH
• glutathion analýza   MeSH
• glutathiondisulfid analýza   MeSH
• imidazoly farmakologie   MeSH
• lidé MeSH
• P-glykoprotein analýza   fyziologie   MeSH
• piperaziny farmakologie   MeSH
• pyridiny farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH