Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin

Abstract

Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well-known anti-malarial agent. In this report, we investigated the effect of artemisinin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Artemisinin markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with low doses of 1α,25-dihydoxyvitamin D 3 [1,25-(OH) 2D 3] or all- trans retinoic acid (all- trans RA). Artemisinin by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that artemisinin potentiated 1,25-(OH) 2D 3-induced cell differentiation predominantly into monocytes and all- trans RA-induced cell differentiation into granulocytes, respectively. Extracellular-regulated kinase (ERK) inhibitors markedly inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH) 2D 3 or all- trans RA, whereas phosphatidylinositol 3-kinase (PI3-K) inhibitors did not. Particularly, protein kinase C (PKC) inhibitors inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH) 2D 3 but not with all- trans RA. Artemisinin enhanced PKC activity and protein level of PKCβI isoform in only 1,25-(OH) 2D 3-treated HL-60 cells. Taken together, these results indicate that artemisinin strongly enhanced 1,25-(OH) 2D 3- and all- trans RA-induced cell differentiation in which PKC is differentially involved in arteminisin-mediated enhancement of leukemia cell differentiation.