TY - JOUR
T1 - Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation
AU - Roth, Michael
AU - Will, Britta
AU - Simkin, Guillermo
AU - Narayanagari, Swathi
AU - Barreyro, Laura
AU - Bartholdy, Boris
AU - Tamari, Roni
AU - Mitsiades, Constantine S.
AU - Verma, Amit
AU - Steidl, Ulrich
PY - 2012/7/12
Y1 - 2012/7/12
N2 - 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 G1 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.
AB - 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 G1 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.
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U2 - 10.1182/blood-2011-12-399667
DO - 10.1182/blood-2011-12-399667
M3 - Article
C2 - 22627766
AN - SCOPUS:84864053179
SN - 0006-4971
VL - 120
SP - 386
EP - 394
JO - Blood
JF - Blood
IS - 2
ER -