title: Deferasirox has strong anti-leukemia activity but may antagonize theanti-leukemia effect of doxorubicin.
abstract: Deferasirox (DFX), in addition to its iron-chelation property, has marked anti-proliferative effects on cancer cells. However, the activity and mechanism by which DFX inhibits acute myeloid leukemia (AML) cells remain to be elucidated. Furthermore, the anti-leukemia effect of combining DFX with currently recommended agents doxorubicin (DOX) and cytosine arabinoside (Ara-C) has not been studied. In this study, we show that DFX significantly reduces the viability of three AML cell lines, HL60, THP1, and WEHI3 and two primary leukemic cells harvested from AML patients. DFX induces cell cycle arrest at G1 phase and apoptosis and inhibits phosphorylation of ERK. We also showed that DFX antagonizes the anti-leukemic effect of DOX. On the contrary, combining DFX with Ara-C created a synergistic effect. Our study confirms the anti-leukemia activity of DFX and provides important information on how to select a partner drug for DFX for the treatment of AML in future clinical trials.
authors.affiliation: a Department of Medical Research , Stem Cell Research Lab., China Medical University Hospital , Taichung , Taiwan.|b Department of Life Science , National Chung Hsing University , Taichung , Taiwan.
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Chang
authors.affiliation: a Department of Medical Research , Stem Cell Research Lab., China Medical University Hospital , Taichung , Taiwan.
authors.forename: Wen-Jyi
authors.initials: WJ
authors.lastname: Lo
authors.affiliation: a Department of Medical Research , Stem Cell Research Lab., China Medical University Hospital , Taichung , Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Huang
authors.affiliation: a Department of Medical Research , Stem Cell Research Lab., China Medical University Hospital , Taichung , Taiwan.
authors.forename: Chaio-Lin
authors.initials: CL
authors.lastname: Lin
authors.affiliation: c Department of Internal Medicine, Division of Hematology and Oncology , China Medical University Hospital , Taichung , Taiwan.
authors.forename: Chiu-Che
authors.initials: CC
authors.lastname: Feng
authors.affiliation: a Department of Medical Research , Stem Cell Research Lab., China Medical University Hospital , Taichung , Taiwan.
authors.forename: Hsin-Ting
authors.initials: HT
authors.lastname: Lin
authors.affiliation: b Department of Life Science , National Chung Hsing University , Taichung , Taiwan.
authors.forename: Hsu-Chen
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: a Department of Medical Research , Stem Cell Research Lab., China Medical University Hospital , Taichung , Taiwan.|c Department of Internal Medicine, Division of Hematology and Oncology , China Medical University Hospital , Taichung , Taiwan.|d China Medical University , Taichung , Taiwan.
authors.forename: Su-Peng
authors.initials: SP
authors.lastname: Yeh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077588:Deferasirox; D004317:Doxorubicin / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D017382:Reactive Oxygen Species; D014230:Triazoles; D004317:Doxorubicin; D007501:Iron; D048049:Extracellular Signal-Regulated MAP Kinases; D000077588:Deferasirox
keywords: AML; Ara-C; Deferasirox; doxorubicin