Synergistic effect of arsenic trioxide and Flt3 inhibition on cells with Flt3 internal tandem duplication

Shinichiro Takahashi, Hideo Harigae, Hisayuki Yokoyama, Izumi Ishikawa, Shouri Abe, Masue Imaizumi, Takeshi Sasaki, Mitsuo Kaku

研究成果: Article査読

17 被引用数 (Scopus)

抄録

Flt3 internal tandem duplication (Flt3-ITD) is a prevalent mutation in acute myeloid leukemia (AML). Flt3-ITD constitutively activates various signaling pathways, including a mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Arsenic trioxide (ATO) and MEK inhibition were recently reported to interact synergistically to induce apoptosis in AML cells. In this study, we aimed to clarify whether ATO and Flt3 inhibition would be a more specific and efficient therapy for Flt3-ITD cells. We demonstrate that the combination of ATO and an Flt3 inhibitor, AG12%, profoundly inhibits the growth of Flt3-ITD cells and induces their apoptosis. We further revealed that this combined treatment potently inhibits the ERK activity that might be responsible for cell growth. Moreover, using the Chou-Talalay method, we observed a synergistic growth-inhibitory effect for ATO and AG12% in Flt3-ITD cells (BaF3-Flt3-ITD, MV4-11, and PL-21 cells), but not in Flt3 wild-type cells (RS4-11 and NB4 cells), for almost all dose ranges tested. Our results provide an experimental basis for a specific and efficient therapy for Flt3-ITD cells that involves combined treatment with Flt3 inhibitors and ATO.

本文言語English
ページ(範囲)256-261
ページ数6
ジャーナルInternational journal of hematology
84
3
DOI
出版ステータスPublished - 2006 10

ASJC Scopus subject areas

  • Hematology

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