Potentiation of 1,25-dihydroxyvitamin D 3-induced differentiation of human promyelocytic leukemia cells into monocytes by costunolide, a germacranolide sesquiterpene lactone

Abstract

Costunolide, a germacranolide sesquiterpene lactone that exists in several medicinal plants, is known to be a possible anti-cancer and chemopreventive agent for tumorigenesis. In this report, we investigated the effect of costunolide on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Costunolide markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with 5 nM 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2D 3). Costunolide by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that costunolide potentiated 1,25-(OH) 2D 3-induced cell differentiation predominantly into monocytes. Inhibitors for PKC, PI3-K, and ERK markedly inhibited HL-60 cell differentiation induced by costunolide in combination with 1,25-(OH) 2D 3. In addition, pretreatment of HL-60 cells with costunolide before the 1,25-(OH) 2D 3 addition also potentiated cell differentiation in a concentration- and time-dependent manner, and the enhanced levels of cell differentiation closely correlated with the inhibitory levels of NF-κB-binding activity by costunolide. These results indicate that PKC, PI3-K, ERK and NF-κB may be involved in 1,25-(OH) 2D 3-mediated cell differentiation enhanced by costunolide.