Antimalarial drug artemisinin depletes erythrocytes by activating apoptotic pathways in zebrafish

Exp Hematol. 2015 Apr;43(4):331-41.e8. doi: 10.1016/j.exphem.2014.11.012. Epub 2015 Jan 10.

Abstract

Despite its extraordinary efficacy, administration of the major antimalarial drug artemisinin leads to anemia, and the underlying cellular and molecular mechanisms are not well understood. Here, we report the effects of artemisinin on erythroid development and apoptosis in zebrafish and human cells. By performing a small-molecule screen with zebrafish embryos, we found that artemisinin treatment depleted red blood cells and slightly decreased definitive hematopoietic stem cells, but had no effect on primitive hematopoietic progenitors. RNA-Seq revealed that artemisinin suppressed a cluster of genes in the heme biosynthesis and globin synthesis pathways. Furthermore, artemisinin induced apoptosis in erythrocytes in zebrafish embryos, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and preferentially acted on differentiated erythrocytes by elevating caspase 8 and caspase 9 activity in differentiated human K562 cells. Consistently, artemisinin suppressed the ectopic expression of erythroid genes in jak2aV581F-injected embryos, a zebrafish model for human polycythemia vera in which the bone marrow makes too many red blood cells. Taken together, our data suggested that artemisinin, in addition to killing parasites, has a direct action on differentiated erythrocytes other than definitive hematopoietic stem cells and causes erythroid apoptosis by interfering with the heme biosynthesis pathway in zebrafish and human cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / pharmacology*
  • Apoptosis*
  • Artemisinins / pharmacology*
  • Erythrocytes / drug effects*
  • Humans
  • K562 Cells
  • Mitochondria / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptors, Death Domain / metabolism
  • Zebrafish

Substances

  • Antimalarials
  • Artemisinins
  • Receptors, Death Domain
  • artemisinine