ironjustice
2013-05-24 15:49:41 UTC
Eltrombopag inhibits the proliferation of leukemia cells via reduction
of intracellular iron and induction of differentiation
Michael Roth1,2, Britta Will2, Guillermo Simkin2, Swathi
Narayanagari2, Laura Barreyro2, Boris Bartholdy2, Roni Tamari3,
Constantine S. Mitsiades4,5, Amit Verma3,6, and Ulrich Steidl2,3
1Division of Pediatric Hematology/Oncology, Children's Hospital at
Montefiore, Bronx, NY;
2Department of Cell Biology, Albert Einstein College of Medicine and
Albert Einstein Cancer Center, Bronx, NY;
3Department of Medicine (Oncology), Albert Einstein College of
Medicine, Bronx, NY;
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
MA;
5Department of Medicine, Harvard Medical School, Boston, MA;
6Department of Developmental and Molecular Biology, Albert Einstein
College of Medicine and Albert Einstein Cancer Center, Bronx, NY
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
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
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.
Submitted December 23, 2011.
Accepted May 15, 2012.
© 2012 by The American Society of Hematology
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
of intracellular iron and induction of differentiation
Michael Roth1,2, Britta Will2, Guillermo Simkin2, Swathi
Narayanagari2, Laura Barreyro2, Boris Bartholdy2, Roni Tamari3,
Constantine S. Mitsiades4,5, Amit Verma3,6, and Ulrich Steidl2,3
1Division of Pediatric Hematology/Oncology, Children's Hospital at
Montefiore, Bronx, NY;
2Department of Cell Biology, Albert Einstein College of Medicine and
Albert Einstein Cancer Center, Bronx, NY;
3Department of Medicine (Oncology), Albert Einstein College of
Medicine, Bronx, NY;
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
MA;
5Department of Medicine, Harvard Medical School, Boston, MA;
6Department of Developmental and Molecular Biology, Albert Einstein
College of Medicine and Albert Einstein Cancer Center, Bronx, NY
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
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
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.
Submitted December 23, 2011.
Accepted May 15, 2012.
© 2012 by The American Society of Hematology
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk