Background: The effects of the A3 adenosine receptor (A3AR) agonist IB-MECA were examined in HL-60 leukemia and in its multidrug-resistant variant HL-60R cells. Methods: Cytotoxicity was evaluated by MTS assays and apoptosis by flow cytometry analyses of DNA fragmentation and phosphatidylserine exposure. The mRNAs of A3AR and inhibitor of apoptosis proteins (IAPs) were determined by RT-PCR. Results: A3AR expression was similar in HL-60 and HL-60R cells. At ≧100 µM, IB-MECA exhibited strong cytotoxic and apoptotic effects in HL-60, but not in HL-60R cells. This activity was not modified by the A3AR antagonist VUF5574, the P-glycoprotein inhibitor verapamil, the adenosine uptake inhibitor NBTI or the anti-Fas antibody ZB4. HL-60R cells showed higher levels of different IAPs than HL-60 cells. IB-MECA 100 µM downregulated HIAP1, NAIP and survivin mRNAs in HL-60, but not in HL-60R cells. Conclusions: The antitumor effects of IB-MECA are not mediated by A3AR in HL-60 cells, where the proapoptotic mechanism of the compound may involve downregulation of IAPs. The resistance of HL-60R cells to IB-MECA may depend on their elevated levels of IAPs.

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