Effects of Iron Deprivation on Multidrug Resistance of Leukemic K562 Cells

Fang, Dingzhu; Yi, Bao; Li, Xiaobin; Liu, Fang; Cai, Kaiming; Gao, Ju; Liao, Qin

doi:10.1159/000287352

Cited by 17 publications

(11 citation statements)

References 36 publications

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“…Recent evidence showing that Pgp, a membrane efflux pump involved in the development of the MDR phenotype (Takara et al ., 2006), is induced in tumour cells exposed to 100 µM dexrazoxane (Riganti et al ., 2008) suggests that, by actively extruding doxorubicin and thus lowering its intracellular concentration, Pgp may be a potential mediator of HIF‐dependent cardioprotection. However, we found that Pgp expression was not affected by dexrazoxane in H9c2 cells despite concomitant HIF activation; this discrepancy may be explained by the cell‐specific response of Pgp to iron deprivation, as suggested by a recent study showing Pgp down‐regulation in leukaemic K562 cells exposed to an iron chelator (Fang et al ., 2010).…”

Section: Discussioncontrasting

confidence: 64%

Retracted: Role of hypoxia‐inducible factors in the dexrazoxane‐mediated protection of cardiomyocytes from doxorubicin‐induced toxicity

Spagnuolo

Recalcati

Tacchini

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSE Iron aggravates the cardiotoxicity of doxorubicin, a widely used anticancer anthracycline, and the iron chelator dexrazoxane is the only agent protecting against doxorubicin cardiotoxicity; however, the mechanisms underlying the role of iron in doxorubicin‐mediated cardiotoxicity and the protective role of dexrazoxane remain to be established. As iron is required for the degradation of hypoxia‐inducible factors (HIF), which control the expression of antiapoptotic and protective genes, we tested the hypothesis that dexrazoxane‐dependent HIF activation may mediate the cardioprotective effect of dexrazoxane. EXPERIMENTAL APPROACH Cell death, protein levels (by immunoblotting) and HIF‐mediated transcription (using reporter constructs) were evaluated in the rat H9c2 cardiomyocyte cell line exposed to low doses of doxorubicin with or without dexrazoxane pretreatment. HIF levels were genetically manipulated by transfecting dominant‐negative mutants or short hairpin RNA. KEY RESULTS Treatment with dexrazoxane induced HIF‐1α and HIF‐2α protein levels and transactivation capacity in H9c2 cells. It also prevented the induction of cell death and apoptosis by exposure of H9c2 cells to clinically relevant concentrations of doxorubicin. Suppression of HIF activity strongly reduced the protective effect of dexrazoxane. Conversely, HIF‐1α overexpression protected against doxorubicin‐mediated cell death and apoptosis also in cells not exposed to the chelator. Exposure to dexrazoxane increased the expression of the HIF‐regulated, antiapoptotic proteins survivin, Mcl1 and haem oxygenase. CONCLUSIONS AND IMPLICATIONS Our results showing HIF‐dependent prevention of doxorubicin toxicity in dexrazoxane‐treated H9c2 cardiomyocytes suggest that HIF activation may be a mechanism contributing to the protective effect of dexrazoxane against anthracycline cardiotoxicity.

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Section: Discussioncontrasting

confidence: 64%

Retracted: Role of hypoxia‐inducible factors in the dexrazoxane‐mediated protection of cardiomyocytes from doxorubicin‐induced toxicity

Spagnuolo

Recalcati

Tacchini

et al. 2011

British J Pharmacology

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“…Some of these studies provide clear evidence about the ability of reduced iron store to accelerate apoptosis, reduce resistance to treatment, and ultimately improve the response to treatment. [ 13 , 31 – 33 ] Although the present findings are in line with the cited studies, none of them have investigated the role of iron in pediatric ALL. In the present study, regardless of the disease's phenotype, the chances of 3-DFS and response to treatment (by the end of the first year) show a definite reduction with the increase in BMIS.…”

Section: Discussionsupporting

confidence: 89%

The relationship between iron bone marrow stores and response to treatment in pediatric acute lymphoblastic leukemia

et al. 2017

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Iron is an intracellular element whose accumulation in the body is associated with tissue damage. This study examines the effect of iron on pediatric acute lymphoblastic leukemia (ALL) and its “response to treatment.” At the end of the first year of treatment, bone marrow iron store (BMIS) was evaluated in children with ALL and the relationship between iron store and minimal residual disease was investigated. Moreover, the 3-year disease-free survival (3-DFS) of patients was determined. Patients’ BMIS were compared with that of subjects with normal bone marrow. The study examined 93 children, including 78 Pre-B and 15 T-cell ALL patients. BMIS did not differ between the children with ALL and those with no evidence of cancer. BMIS was increased in 26.6% of patients at the end of the first year of treatment. Drug resistance and BM relapses were more prevalent in cases with high BMIS in both Pre-B and T-cell groups. Bone marrow iron store is not considered a risk factor for childhood ALL. However, high levels of BMIS are associated with poor response to treatment and the risk of relapse. Bone marrow iron store control during treatment can therefore help achieve better outcomes and improve the chances of recovery.

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“…In addition to its anti‐tumourigenic effects, it was observed that Dp44mT could also be used to overcome multi‐drug resistance (Whitnall et al ., ). These observations are supported by evidence that iron chelators can decrease the expression of multi‐drug resistance genes, including MDR1 (Fang et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo

Ford

Obeidy

Lovejoy

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEGrowing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti-tumour activity, although whether iron chelators show activity against oesophageal cancer is not known. EXPERIMENTAL APPROACHThe effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed. KEY RESULTSDeferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels. CONCLUSIONS AND IMPLICATIONSThe clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.

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Effects of Iron Deprivation on Multidrug Resistance of Leukemic K562 Cells

Cited by 17 publications

References 36 publications

Retracted: Role of hypoxia‐inducible factors in the dexrazoxane‐mediated protection of cardiomyocytes from doxorubicin‐induced toxicity

Retracted: Role of hypoxia‐inducible factors in the dexrazoxane‐mediated protection of cardiomyocytes from doxorubicin‐induced toxicity

The relationship between iron bone marrow stores and response to treatment in pediatric acute lymphoblastic leukemia

Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo

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