Study of Resistance Mechanisms of All-trans Retinoic Acid in Acute Promyelocytic Leukemia

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We present here the relationship between all-trans retinoic acid (ATRA)-resistance and P-glycoprotein (P-gp)-associated multidrug resistance (MDR) in acute promyelocytic leukemia (APL). Cells used in this study were NB4 (negative for MDR1, MDR related protein and lung resistant protein), ATRA-resistant NB4 (NB4/RA), MDR1 cDNA-transduced NB4 (NB4/MDR) and MDR1 cDNA-transduced NB4/RA (NB4/RA/MDR), and blast cells from 10 patients with APL. Intracellular ATRA accumulation was determined by the characteristic emission curve of ATRA, which was excited by ultra violet in multi-laser-equipped flow cytometer. The apoptosis- and differentiation-introducing effects of ATRA were determined by CD11b, NBT reduction activity, cell cycle distribution and morphology.While NB4/MDR and NB4/RA/MDR cells accumulated less Rhodamine-123 (Rh123) than NB4 and NB4/RA cells, respectively, there is no difference in the intracellular ATRA concentration between them. PSC833, a MDR modifier, increased the intracellular accumulation of Rh123 in NB4/MDR and NB4/RA/MDR cells, but not of ATRA. The expression of CD11b, the NBT reduction activity, the proportion of apoptotic cells and the morphology were not different between NB4 and NB4/MDR cells and between NB4/RA and NB4/RA/MDR cells. Similar results were obtained in the analysis of APL cells from patients relapsed after ATRA-induced complete remission.Although there are a few reports that ATRA-resistant APL cells expressed more P-gp than ATRA-sensitive ones, we here directly show that the expression of P-gp does not influence the intracellular concentration of ATRA and that P-gp and ATRA-resistance independently exist.