Arsenic trioxide circumvents multidrug resistance based on different mechanisms in human leukemia cell lines

To determine the antitumor effect of arsenic trioxide (As(2)O(3)) on multidrug-resistant cells, we applied 3 human leukemia cell lines: daunorubicin (DNR)-resistant cell line K562/D1-9, which overexpresses p-glycoprotein (Pgp); DNR and 1-beta-D-arabinofuranosylcytosine (Ara-C) double-resistant cell line HL60/AD, which overexpresses multidrug resistance-associated protein (MRP1); and Bcl-2-transfected pre-B lineage leukemia cell line 697/Bcl-2. Interestingly, K562/D1-9 showed collateral sensitivity. Only HL60/AD showed small cross resistance, but 697/Bcl-2 had no resistance to As(2)O(3). An intracellular content of glutathione (GSH) played a critical role in sensitivity to As(2)O(3). Buthionine-sulfoximine (BSO), which reduces the GSH content, not only increased the AS(2)O(3) sensitivity but also conquered the MRP1- related cross resistance in HL60/AD. In conclusion, AS(2)O(3) was effective in all 3 cell lines, suggesting that AS(2)O(3) may be a promising agent for the treatment of multidrug-resistant leukemia.