title: Synergistic inhibitory effects of deferasirox in combination with decitabine on leukemia cell lines SKM-1, THP-1, and K-562.
abstract: A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS. In this study, we aimed to explore this clinical phenomena in vitro, by exploring the synergistic effect of the iron chelator Deferasirox (DFX) and the DNA methyl transferase inhibitor Decitabine (DAC) in the leukemia cell lines SKM-1, THP-1, and K-562. Treatment with both DFX or DAC promoted apoptosis, induced cell cycle arrest, and inhibited proliferation in all three of these cell lines. The combination of DFX and DAC was much greater than the effect of using either drug alone. DFX showed a synergistic effect with DAC on cell apoptosis in all three cell lines and on cell cycle arrest at the G0/G1 phase in K-562 cells. DFX decreased the ROS levels to varying degrees. In contrast, DAC increased ROS levels and an increase in ROS was also noted when the two drugs were used in combination. Treatment of cells with DAC induced re-expression of ABAT, APAF-1, FADD, HJV, and SMPD3, presumably through demethylation. However the combination of DAC and DFX just had strong synergistic effect on the re-expression of HJV.
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Nianyi
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qinfen
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077209:Decitabine; D000077588:Deferasirox; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D001565:Benzoates; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D014230:Triazoles; D000077209:Decitabine; D001374:Azacitidine; D000077588:Deferasirox
keywords: decitabine; deferasirox; demethylation; iron chelation therapy; synergistic effect