The Impact of Iron Chelators on the Biology of Cancer Stem Cells

Szymonik, Julia; Wala, Kamila; Górnicki, Tomasz; Saczko, Jolanta; Pencakowski, Bartosz; Kulbacka, Julita

doi:10.3390/ijms23010089

Cited by 20 publications

(15 citation statements)

References 116 publications

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“…MAPK/ERK signaling activated ferritin and regulated NCAO4-mediated iron phagocytosis and HO1 expression, which provided potential therapeutic targets for AKI management ( Su et al, 2019 ). Deferiprone has been used in patients with high ferrous load from repeated transfusions, but there have been no studies related to the application of deferiprone for the prevention or treatment of AKI due to rhabdomyolysis ( Szymonik et al, 2021 ). Baicalein, an important active ingredient in the Chinese herb Scutellaria baicalensis, attenuated myocardial ischemia-reperfusion-induced AKI by regulating the B-cell lymphoma-2 (BCL2), extracellular signal-regulated kinase 1/2, and BCL2 associated X (BAX) activation of protein kinase B (PKB) ( Lai et al, 2016 ; Szymonik et al, 2021 ).…”

Section: Treatment Of Ferroptosis In Acute Kidney Injurymentioning

confidence: 99%

“…Deferiprone has been used in patients with high ferrous load from repeated transfusions, but there have been no studies related to the application of deferiprone for the prevention or treatment of AKI due to rhabdomyolysis ( Szymonik et al, 2021 ). Baicalein, an important active ingredient in the Chinese herb Scutellaria baicalensis, attenuated myocardial ischemia-reperfusion-induced AKI by regulating the B-cell lymphoma-2 (BCL2), extracellular signal-regulated kinase 1/2, and BCL2 associated X (BAX) activation of protein kinase B (PKB) ( Lai et al, 2016 ; Szymonik et al, 2021 ). It has been shown that baicalein can also enhance cellular resistance to ferroptosis by limiting iron accumulation and lipid peroxidation in cells, which makes it a promising therapeutic agent for ferroptosis-related tissue damage ( Xie et al, 2016b ).…”

Section: Treatment Of Ferroptosis In Acute Kidney Injurymentioning

confidence: 99%

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The Role of Ferroptosis in Acute Kidney Injury

Zhang

Wang

Yuan

et al. 2022

Front. Mol. Biosci.

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Ferroptosis is a novel cell death method discovered in recent years. It is usually accompanied by massive accumulations of iron and lipid peroxidation during cell death. Recent studies have shown that ferroptosis is closely associated with the pathophysiological processes of many diseases, such as tumors, neurological diseases, localized ischemia-reperfusion injury, kidney injury, and hematological diseases. How to intervene in the incidence and development of associated diseases by regulating the ferroptosis of cells has become a hot topic of research. This article provides a review of the role of ferroptosis in the pathogenesis and potential treatment of acute kidney injury.

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Section: Treatment Of Ferroptosis In Acute Kidney Injurymentioning

confidence: 99%

Section: Treatment Of Ferroptosis In Acute Kidney Injurymentioning

confidence: 99%

The Role of Ferroptosis in Acute Kidney Injury

Zhang

Wang

Yuan

et al. 2022

Front. Mol. Biosci.

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“…A truncated isoform of NDRG1 has been observed in prostate cancer cell lines but not normal cell lines, this could explain Frontiers in Molecular Biosciences frontiersin.org the contradictory roles observed in cells, the full length isoform may be responsible for the tumour suppressor roles of NDRG1 and the truncated version for the oncogenic roles, this warrants further investigation (Park et al, 2018). In addition to NDRG1 upregulation, iron chelation can inhibit cancer cell stemness (Szymonik et al, 2021). Cancer stem cells present a roadblock to full patient recovery as their capacity for self-renewal can fuel metastasis and drug resistance (Yu et al, 2012b;Szymonik et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Novel iron chelator SK4 demonstrates cytotoxicity in a range of tumour derived cell lines

Abdelaal

Carter

Panayiotides

et al. 2022

Front. Mol. Biosci.

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Iron is an essential micronutrient due to its involvement in many cellular processes including DNA replication and OXPHOS. Tumors overexpress iron metabolism linked proteins which allow for iron accumulation driving high levels of proliferation. Our group has designed novel iron chelator SK4 which targets cancer’s “iron addiction.” SK4 comprises of two key moieties: an iron chelation moiety responsible for cytotoxicity and an amino acid moiety which allows entry through amino acid transporter LAT1. We selected LAT1 as a route of entry as it is commonly overexpressed in malignant tumors. SK4 has previously demonstrated promising results in an in vitro model for melanoma. We hypothesized SK4 would be effective against a range of tumor types. We have screened a panel of tumor-derived cell lines from different origins including breast, prostate, ovarian and cervical cancer for SK4 sensitivity and we have found a range of differential sensitivities varying from 111.3 to >500 μM. We validated the iron chelation moiety as responsible for inducing cytotoxicity through control compounds; each lacking a key moiety. Following the screen, we conducted a series of assays to elucidate the mechanism of action behind SK4 cytotoxicity. SK4 was shown to induce apoptosis in triple negative breast cancer cell line MDA MB 231 but not ovarian cancer cell line SKOV3 suggesting SK4 may induce different modes of cell death in each cell line. As MDA MB 231 cells harbor a mutation in p53, we conclude SK4 is capable of inducing apoptosis in a p53-independent manner. SK4 upregulated NDRG1 expression in MDA MB 231 and SKOV3 cells. Interestingly, knockdown of NDRG1 antagonized SK4 in MDA MB 231 cells but not SKOV3 cells suggesting SK4’s mechanism of action may be mediated through NDRG1 in MDA MB 231 cells. In conclusion, we have shown tagging iron chelators with an amino acid moiety to allow entry through the LAT1 transporter represents a double pronged approach to cancer therapy, targeting “iron addiction” and amino acid metabolism dysregulation.

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“…In recent years, an increasing number of studies have found that the inevitability of treatment resistance and recurrence in GBM may be due to the presence of cancer stem-like cells (CSCs) ( 32 ). Owing to the nature of enhanced resistance to conventional chemo/radiotherapy and metastasis, CSCs have been proposed as promising targets for cancer eradication ( 33 ).…”

Section: Regulation Of Ferroptosis In Gliomamentioning

confidence: 99%

“…This alteration in iron metabolism is likely to be related to the treatment resistance of GBM CSCs. Expression of stemness-related markers has been proven to be affected by iron chelators, therefore targeting iron metabolic processes in CSCs is promising for reducing tumor cell therapeutic resistance ( 32 ).…”

Section: Regulation Of Ferroptosis In Gliomamentioning

confidence: 99%

Emerging roles of ferroptosis in glioma

et al. 2022

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Glioma is the most common primary malignant tumor in the central nervous system, and directly affects the quality of life and cognitive function of patients. Ferroptosis, is a new form of regulated cell death characterized by iron-dependent lipid peroxidation. Ferroptosis is mainly due to redox imbalance and involves multiple intracellular biology processes, such as iron metabolism, lipid metabolism, and antioxidants synthesis. Induction of ferroptosis could be a new target for glioma treatment, and ferroptosis-related processes are associated with chemoresistance and radioresistance in glioma. In the present review, we provide the characteristics, key regulators and pathways of ferroptosis and the crosstalk between ferroptosis and other programmed cell death in glioma, we also proposed the application and prospect of ferroptosis in the treatment of glioma.

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The Impact of Iron Chelators on the Biology of Cancer Stem Cells

Cited by 20 publications

References 116 publications

The Role of Ferroptosis in Acute Kidney Injury

The Role of Ferroptosis in Acute Kidney Injury

Novel iron chelator SK4 demonstrates cytotoxicity in a range of tumour derived cell lines

Emerging roles of ferroptosis in glioma

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