Yazarlar : Roth M, Will B, Simkin G, Narayanagari S,et al

Yayın : Blood

Yayın Yılı : 2012

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/22627766

Konu : Diğer

Literatür İçeriği :  

Abstract

Eltrombopag is a small molecule, non-peptide thrombopoietin receptor (TPO-R) agonist and has recently been approved for the treatment of thrombocytopenia in patients with chronic ITP. Prior studies have shown eltrombopag stimulates megakaryopoiesis in bone marrow cells from patients with AML and MDS, and further suggested it may inhibit leukemia cell growth. Here, we studied the effects of eltrombopag on leukemic cell proliferation and the mechanism of its anti-proliferative effects. We found that eltrombopag leads to a decreased cell division rate, a block in G1 phase of cell cycle, and increased differentiation in human as well as murine leukemia cells. As eltrombopag is species-specific in that it can only bind the TPO-R in human and primate cells, these findings further suggested that the anti-leukemic effect is independent of the TPO-R. We found that treatment with eltrombopag leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the anti-proliferative and differentiation-inducing effects of eltrombopag, demonstrating that the anti-leukemic effects of eltrombopag are mediated through modulation of intracellular iron content. Finally, determination of eltrombopag's anti-leukemic activity in vivo shows its ability to prolong survival in two mouse models of leukemia.

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