Retinoids increase idarubicin cytotoxicity in human myeloid leukemia cell lines

All-trans-retinoic acid (ATRA) has proven useful in acute promyelocytic leukemia (APL). In order to reduce the side effects and to improve the efficacy of this compound, conventional chemotherapy, and anthracyclines in particular, are frequently added either during remission induction or in consolidation therapy. In this study we aimed at investigating the rationale of the combination of ATRA plus idarubicin in two human leukemic cell lines, HL-60 and K562, that display a different sensitivity to ATRA treatment. The effects of ATRA were compared with those of two clinically active retinoids, 13-cis-retinoic acid (13-cis-RA) and 9-cis-retinoic acid (9-cis-RA). Both in HL-60 and in K562 cells, the majority of the combinations of ATRA and idarubicin were synergistic, while the combinations with 9-cis-RA and 13-cis-RA were more effective in HL-60 and K562 cells, respectively. A 72 h pre-incubation with retinoids was able to further increase the cytotoxicity of ATRA plus idarubicin in the two cell lines. Intracellular idarubicin accumulation was enhanced by retinoids, as demonstrated by a cytofluorimetric method. Our results could contribute to provide a rationale for ATRA plus idarubicin combinations not only in APL but also in acute leukemia of other cytotypes.