title: Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation.
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 antileukemic 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.
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, 1300 Morris Park Ave, Bronx, NY 10461, USa.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
authors.forename: Britta
authors.initials: B
authors.lastname: Will
authors.forename: Guillermo
authors.initials: G
authors.lastname: Simkin
authors.forename: Swathi
authors.initials: S
authors.lastname: Narayanagari
authors.forename: Laura
authors.initials: L
authors.lastname: Barreyro
authors.forename: Boris
authors.initials: B
authors.lastname: Bartholdy
authors.forename: Roni
authors.initials: R
authors.lastname: Tamari
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011720:Pyrazoles / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D007501:Iron; C520809:eltrombopag