Effects of selective RAR or/and RXR retinoids on the proliferation and differentiation of NB4 cells and their mechanisms

Objective To investigate the effects of RARβ selective agonist and RARα antagonist (RARβ+/RARα-) BMS453 in combination with RXR selective agonist (RXR+) BMS649 on the proliferation and differentiation of NB4 cells ,and illustrate the mechanism. Methods The proliferation and differentiation of NB4 cells were detected by cell count, morphological observation, NBT reduction assay, immunofluorescence analysis, flow cytometry and RT-PCR. Results BMS453 in combination with BMS649 could significantly inhibited the growth of NB4 cell in the manner of dose and time dependence. NB4 cells treated with BMS453 and BMS649 were irreversibly committed to morphologically and functionally more differentiated granulocytic cells. When NB4 cells were treated with BMS453 and BMS649 for 0, 1, 3, 12, 24 and 48?h, RARα,RARβ and RXRα expressions were up regulated at 1 h and 3h, respectively. As compared to ATRA, the situations had no significant difference. In contrast, BMS453 or BMS649 alone was ineffective on NB4 cells. Conclusion BMS453(RARβ+/RARα-) in combination with BMS649 (RXR+) significantly and synergistically inhibit proliferation of NB4 cells and induce them into granulocytic differentiation, the mechanism of which may be mediated by the AF-2 activity of RXR.