Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

Michael Roth, Britta Will, Guillermo Simkin, Swathi Narayanagari, Laura Barreyro, Boris Bartholdy, Roni Tamari, Constantine S. Mitsiades, Amit Verma, Ulrich Steidl

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects.We found that EP leads to a decreased cell division rate, a block in G 1 phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the anti-leukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia.

Original languageEnglish (US)
Pages (from-to)386-394
Number of pages9
JournalBlood
Volume120
Issue number2
DOIs
StatePublished - Jul 12 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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