Deferasirox shows in vitro and in vivo antileukemic effects on murine leukemic cell lines regardless of iron status

Lee, Dae-Hyoung; Jang, Pil‐Sang; Chung, Nak Gyun; Cho, Bin; Jeong, Dae Chul; Kim, Hack Ki

doi:10.1016/j.exphem.2013.02.004

Cited by 19 publications

(13 citation statements)

References 30 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20 mg/kg/day) with a tumor size smaller. [ 35 ] Iron chelation therapy with DFX induces complete remission in a patient with chemotherapy-resistant acute monocytic leukemia [ 36 ] DFX (5 to 50 μM) induces apoptosis in myeloid leukemia cells by targeting caspase. [ 37 ] DFX (50 μM) induces apoptosis and inhibits NFKB activity in K562 leukemia cells independently of iron deprivation.…”

Section: Introductionmentioning

confidence: 99%

Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

et al. 2016

View full text Add to dashboard Cite

BackgroundOvercoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia.ResultsUnder experimental normoxic condition (21 % O2), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3 % O2), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired.ConclusionsTaken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2074-y) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%

Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…ICAs have been used to treat transfusional iron overload and overcome the complications of SIO, and are considered potential anti-cancer agents [ 15 , 16 ]. Several studies support the anti-leukemic effects of ICAs [ 3 , 12 , 13 , 17 , 18 , 19 , 20 ]. This was based on evidence of anti-tumor effects, including the inhibition of proliferation and differentiation via inhibited DNA synthesis and apoptosis induction through caspase 3 and 9 [ 18 , 19 , 20 ].…”

Section: Discussionmentioning

confidence: 96%

“…Hematological malignancies such as acute leukemia require frequent blood transfusions [ 1 ]. Multiple blood transfusions may lead to secondary iron overload (SIO), which promotes cancer cell growth and induces deleterious effects on the innate immune system [ 2 , 3 , 4 ]. An iron-chelating agent (ICA) is used to minimize the adverse effects of iron overload in patients with SIO who require repeated blood transfusions [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, studies on the potential anti-leukemic effects of DFX in lymphoid malignancies remain limited. Previously, we reported that DFX has anti-leukemic effects in murine lymphoid leukemia cell lines [ 3 ]. In this study, we sought to validate the anti-leukemic activity of DFX in murine lymphoid leukemia cell lines, and clarify the intracellular apoptotic mechanisms that are responsible for the potential anti-leukemic effect.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-leukemic properties of deferasirox via apoptosis in murine leukemia cell lines

et al. 2015

Self Cite

View full text Add to dashboard Cite

BackgroundAlthough deferasirox (DFX) is reported to have anti-tumor effects, its anti-leukemic activity remains unclear. We evaluated the effect of DFX treatment on two murine lymphoid leukemia cell lines, and clarified the mechanisms underlying its potential anti-leukemic activity.MethodsL1210 and A20 murine lymphoid leukemia cell lines were treated with DFX. Cell viability and apoptosis were evaluated by the 3-(4,5-dimethylthaizol-2-yl)-5-(3-carboxymethylphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and fluorescence-activated cell sorting (FACS) analysis, respectively. Immunoblotting was performed to detect the expression of key apoptotic proteins.ResultsIn dose- and time-dependent manner, DFX decreased viability and increased apoptosis of murine leukemic cells. Fas expression was significantly higher in A20 cells than in L1210 cells at all DFX concentrations tested. Although both cell lines exhibited high caspase 3 and caspase 9 expression, a critical component of the intrinsic mitochondrial apoptotic pathway, expression was greater in L1210 cells. In contrast, caspase 8, a key factor in the extrinsic apoptotic pathway, showed greater expression in A20 cells. Cytochrome c expression was significantly higher in L1210 cells. In both cell lines, co-treatment with ferric chloride and DFX diminished the expression of these intracellular proteins, as compared to DFX treatment alone.ConclusionTreatment with DFX increased caspase-dependent apoptosis in two murine lymphoid leukemia cell lines, with differing apoptotic mechanisms in each cell line.

show abstract

“…Iron chelators have been used for the treatment of iron-overload disease [18]. DFO and DFX are two licensed iron chelators commonly used for iron-overload disease [19,20]. DFO has been reported to inhibit the growth of cervical cancer cells [11], but it failed to prevent the growth of cervical carcinoma xenografts in mice [12].…”

Section: Discussionmentioning

confidence: 99%

Deferasirox Shows Inhibition Activity Against Cervical Cancer in vitro and in vivo

Zhou

Cui

Kuang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Iron depletion may be a novel therapeutic strategy for cancer. As an oral iron chelator, deferasirox (DFX) is expected to become an anticancer agent. This study aimed to assess the effects of DFX on cervical cancer.Methods: The effects of DFX on cellular iron metabolism, cell viability, cell cycle and apoptosis, and cell invasion were assessed in two cervical cancer cell lines. The effects of DFX on the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) were examined. The expression of N-myc downstream regulated gene 1 (NDRG1) and c-myc, and the activation of the MEK/ERK signaling pathway were investigated. The effect of DFX on tumor burden was assessed using a murine xenograft model.Results: DFX decreased the viability of HeLa and SiHa cells, induced cell cycle and apoptosis, and decreased cell invasion. The expression of NDRG1 was upregulated while that of c-myc was downregulated. The activation of the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth with no serious side effects, decreased ferritin levels in nude mice serum, and decreased ferritin heavy chain (FTH) expression in xenograft tumor tissue.Conclusions: The inhibitory effect of DFX on cervical cancer cells and xenograft tumor growth was related to its effective depletion of iron in tumor cells. These results demonstrate that DFX has potential as a therapeutic agent for cervical cancer.

show abstract

Deferasirox shows in vitro and in vivo antileukemic effects on murine leukemic cell lines regardless of iron status

Cited by 19 publications

References 30 publications

Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

Anti-leukemic properties of deferasirox via apoptosis in murine leukemia cell lines

Deferasirox Shows Inhibition Activity Against Cervical Cancer in vitro and in vivo

Contact Info

Product

Resources

About