title: Synergistic effect of arsenic trioxide and flt3 inhibition on cells with flt3 internal tandem duplication.
abstract: 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, AG1296, 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 AG1296 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.
authors.affiliation: Department of Infection Control and Laboratory Diagnostics, Tohoku University Graduate School of Medicine, Sendai, Japan. shintak@mail.tains.tohoku.ac.jp
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Izumi
authors.initials: I
authors.lastname: Ishikawa
authors.forename: Shouri
authors.initials: S
authors.lastname: Abe
authors.forename: Masue
authors.initials: M
authors.lastname: Imaizumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kaku
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D000077237:Arsenic Trioxide