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The present study was conducted to verify whether caffeine is beneficial for improving leukaemia therapy.Co-treatment with adaphostin (a Bcr/Abl inhibitor) was found to potentiate caffeine induced Fas/FasL up-regulation.Although adaphostin did not elicit ASK1 (apoptosis signal-regulating kinase 1)-mediated phosphorylation of p38 MAPK (mitogenactivated protein kinase) and JNK (c-Jun N-terminal kinase), co-treatment with adaphostin notably increased p38 MAPK/JNK activation in caffeine-treated cells.Suppression of p38 MAPK and JNK abrogated Fas/FasL up-regulation in caffeine-and caffeine/adaphostin-treated cells.Compared with caffeine, adaphostin markedly suppressed Akt/ERK (extracellular-signal-regulated kinase)-mediated MKP-1 (MAPK phosphatase 1) protein expression in K562 cells.MKP-1 down-regulation eventually elucidated the enhanced effect of adaphostin on p38 MAPK/JNK activation and subsequent Fas/FasL up-regulation in caffeine-treated cells.Knockdown of p38 MAPK and JNK1, ATF-2 (activating transcription factor 2) and c-Jun by siRNA (small interfering RNA) proved that p38 MAPK/ATF-2 and JNKl/c-Jun pathways were responsible for caffeine-evoked Fas/FasL up-regulation.Moreover, Ca and ROS (reactive oxygen species) were demonstrated to be responsible for ASK1 activation and Akt/ERK inactivation respectively in caffeineand caffeine/adaphostin treated cells.Likewise, adaphostin functionally enhanced caffeine-induced Fas/FasL upregulation in leukaemia cells that expressed Bcr/Abl.Taken together, the results of the present study suggest a therapeutic strategy in improving the efficacy of adaphostin via Fas-mediated death pathway activation in Bcr/Ablpositive leukaemia.