Effect of retinoic acid isomers on proliferation, differentiation and PML relocalization in the APL cell line NB4.

Retinoic acids exert a wide physiological role in development and differentiation. Retinoic acids have also been used in the treatment of human cancers, particularly in acute promyelocytic leukemia (APL). A structure-function relationship of the RA isomers in terms of clinical effect has been observed since all-trans retinoic acid (ATRA) induces a high complete remission rate while 13-cis retinoic acid (13-cis RA) shows much poorer effect. In this study, we examined the effect of RA isomers, including ATRA, 13-cis RA and 9-cis RA, on the proliferation and differentiation of NB4 cells. A number of parameters such as cell growth curve, dynamics of cell cycle, expression of clusters of differentiation and reduction of nitro blue tetrazolium (NBT) as well as immunofluorescence staining of PML were used to evaluate the effects of three isomers at two concentrations (10(-8) M and 10(-7) M). It has been shown that during the first 48 h of RA treatment, the APL cell differentiation was coupled with the cell proliferation. Although similar effects of proliferation inhibition and differentiation induction were observed among the three isomers at 10(-7) M, significant differences appeared at a concentration of 10(-8) M, 9-cis RA showed a higher activity than that of ATRA, while ATRA showed better results than 13-cis RA. Our results provide further evidence that 9-cis RA could be a promising molecule in differentiation induction of malignant cells.