Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin.
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 1 alpha,25-dihydoxyvitamin D(3) [1,25-(OH)(2)D(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)(2)D(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)(2)D(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)(2)D(3) but not with all-trans RA. Artemisinin enhanced PKC activity and protein level of PKC beta I isoform in only 1,25-(OH)(2)D(3)-treated HL-60 cells. Taken together, these results indicate that artemisinin strongly enhanced 1,25-(OH)(2)D(3)- and all-trans RA-induced cell differentiation in which PKC is differentially involved in arteminisin-mediated enhancement of leukemia cell differentiation.
Kim
Seung Hyun
SH
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju 500-757, South Korea.
Kim
Hyeong Joon
HJ
Kim
Tae Sung
TS
D037621:Artemisinins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000473:pathology*; D009536:Niacinamide / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D037621:Artemisinins; D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; D009536:Niacinamide; D014212:Tretinoin; C031327:artemisinin; D011493:Protein Kinase C