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      Iron and leukemia: new insights for future treatments

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          Abstract

          Iron, an indispensable element for life, is involved in all kinds of important physiological activities. Iron promotes cell growth and proliferation, but it also causes oxidative stress damage. The body has a strict regulation mechanism of iron metabolism due to its potential toxicity. As a cancer of the bone marrow and blood cells, leukemia threatens human health seriously. Current studies suggest that dysregulation of iron metabolism and subsequent accumulation of excess iron are closely associated with the occurrence and progress of leukemia. Specifically, excess iron promotes the development of leukemia due to the pro-oxidative nature of iron and its damaging effects on DNA. On the other hand, leukemia cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide new insights for approaches to the treatment of leukemia. This review summarizes physiologic iron metabolism, alternations of iron metabolism in leukemia and therapeutic opportunities of targeting the altered iron metabolism in leukemia, with a focus on acute leukemia.

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          Most cited references143

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          Ferroptosis, a new form of cell death: opportunities and challenges in cancer

          Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.
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            Iron and cancer: more ore to be mined.

            Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.
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              Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib.

              The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC). In our report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors. © 2013 UICC.
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                Author and article information

                Contributors
                wangfang1@mail.nwpu.edu.cn
                lvhh2017@nwpu.edu.cn
                zhao000bin@mail.nwpu.edu.cn
                zlf19900919@mail.nwpu.edu.cn
                wangshenghang@mail.nwpu.edu.cn
                Luojie16@mail.nwpu.edu.cn
                liujunyu@mail.nwpu.edu.cn
                shangpeng@nwpu.edu.cn
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                13 September 2019
                13 September 2019
                2019
                : 38
                : 406
                Affiliations
                [1 ]ISNI 0000 0001 0307 1240, GRID grid.440588.5, School of Life Science, , Northwestern Polytechnical University, ; Xi’an, 710072 China
                [2 ]Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, 518057 China
                [3 ]ISNI 0000 0001 0307 1240, GRID grid.440588.5, Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, , Northwestern Polytechnical University, ; Xi’an, 710072 China
                Author information
                http://orcid.org/0000-0001-5418-6240
                Article
                1397
                10.1186/s13046-019-1397-3
                6743129
                31519186
                4ab43432-8107-4f8d-83fc-acc76366600d
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 May 2019
                : 27 August 2019
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 51777171
                Award ID: 81803032
                Award Recipient :
                Funded by: the Fundamental Research Funds for the Central Universities
                Award ID: 3102017OQD111
                Award Recipient :
                Funded by: the Northwestern Polytechnical University Foundation for Fundamental Research
                Award ID: 3102018JGC012
                Award Recipient :
                Funded by: Science and Technology Planning Project of Shenzhen of China
                Award ID: JCYJ20170412140904406
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                leukemia,iron,reactive oxygen species,ferroptosis,iron-based nanoparticles
                Oncology & Radiotherapy
                leukemia, iron, reactive oxygen species, ferroptosis, iron-based nanoparticles

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