Greater synergism of retinoic acid receptor (RAR) agonists with vitamin D 3 than that of retinoid X receptor (RXR) agonists with regard to growth inhibition and differentiation induction in monoblastic leukemia cells

Abstract

Retinoids and 1α,25-dihydroxyvitamin D 3 (VD 3) cooperatively induce the differentiation of myeloid leukemia cells. We investigated the role of retinoid receptors (RARs and RXRs) in the combined effects of retinoids and VD 3 on growth inhibition and differentiation induction in human monoblastic leukemia U937 cells by using RAR- or RXR-selective retinoids. An isobologram analysis showed that both combinations were synergistic with regard to inhibiting the proliferation, and RAR agonists exhibited greater synergism with VD 3 than did RXR agonists. RXR agonists alone induced nitroblue tetrazolium (NBT) reduction and expression of CD11b in U937 cells, whereas RAR agonists alone did not. On the other hand, RAR agonists and RXR agonists enhanced the differentiation induced by VD 3, but RXR agonists required higher concentrations. An RAR antagonist inhibited the differentiation induced by RAR agonists plus VD 3, but not that induced by RXR agonists plus VD 3. Thus, RARs and RXRs act differently in their synergism with VD 3. RAR agonists are more potent than RXR agonists with regard to synergism with VD 3, and their combination may be useful in differentiation therapy against myeloid leukemia.