Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2

Kuban–Jankowska, Alicja; Sahu, Kamlesh Kumar; Górska‐Ponikowska, Magdalena; Tuszyński, Jack A.; Woźniak, Michał

doi:10.21873/anticanres.11886

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…34,37,38 The observation that iron chelation precipitates timedependent detrimental effects against nonmetastatic (MCF-7) and metastatic (MDA-MB-231) breast cancer cells (Figures 6 and 7) is consistent with previous reports which have shown that DFO treatment minimizes cell migration and wound healing potential in MCF-7 cells 34 and that it decreases the viability and proliferation of breast cancer cells. 43 This is in agreement with the observation that DFO-induced LIP depletion increases the susceptibility of cell lines like K562 to doxorubicin 38 and that DFO treatment in TP53-MDA-MB-231 and TP53-MCF-7 results in pronounced epigenetic alterations that associate with increased apoptosis and enhanced sensitivity to doxorubicin and cisplatin. 44 Increased expression of g-H2AX and decreased expression of surviving with increasing concentration of DFO as shown in Figure 6 further confirm the apoptotic potential of iron chelation.…”

Section: Discussionsupporting

confidence: 89%

High-Dose Deferoxamine Treatment Disrupts Intracellular Iron Homeostasis, Reduces Growth, and Induces Apoptosis in Metastatic and Nonmetastatic Breast Cancer Cell Lines

Bajbouj

Shafarin

Hamad

2018

Technol Cancer Res Treat

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Mounting evidence suggest that iron overload enhances cancer growth and metastasis; hence, iron chelation is being increasingly used as part of the treatment regimen in patients with cancer. Now whether iron chelation depletes intracellular iron and/or disrupts intracellular iron homeostasis is yet to be fully addressed. MCF-7 and MDA-MB-231 breast cancer cells treated with increasing concentrations of the iron chelator deferoxamine were assessed for intracellular iron status, the expression of key proteins involved in iron metabolism, cell viability, growth potential, and apoptosis at different time points following treatment. Treatment with deferoxamine at 1, 5, or 10 μM for 24 or 48 hours, while not leading to significant changes in intracellular labile iron content, upregulated the expression of hepcidin, ferroportin, and transferrin receptors 1 and 2. In contrast, deferoxamine at 30, 100, or 300 μM for 24 hours induced a significant decrease in intracellular labile iron, which was associated with increased expression of hepcidin, ferritin, and transferrin receptors 1 and 2. At 48 hours, there was an increase in intracellular labile iron, which was associated with a significant reduction in hepcidin and ferritin expression and a significant increase in ferroportin expression. Although low-dose deferoxamine treatment resulted in a low to moderate decrease in MCF-7 cell growth, high-dose treatment resulted in a significant and precipitous decrease in cell viability and growth, which was associated with increased expression of phosphorylated Histone 2A family member X and near absence of survivin. High-dose deferoxamine treatment also resulted in a very pronounced reduction in wound healing and growth in MDA-MB-231 cells. These findings suggest that high-dose deferoxamine treatment disrupts intracellular iron homeostasis, reduces cell viability and growth, and enhances apoptosis in breast cancer cells. This is further evidence to the potential utility of iron chelation as an adjunctive therapy in iron-overloaded cancers.

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Section: Discussionsupporting

confidence: 89%

High-Dose Deferoxamine Treatment Disrupts Intracellular Iron Homeostasis, Reduces Growth, and Induces Apoptosis in Metastatic and Nonmetastatic Breast Cancer Cell Lines

Bajbouj

Shafarin

Hamad

2018

Technol Cancer Res Treat

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“…Preclinical models showed variable uptake of fluorescently-labeled transferrin at metastatic sites. Treatment with DFO [ 30 , 76 ] increased the uptake of transferrin conjugates by breast cancer cells in vitro and in a mouse model of metastatic breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting

Fontana,

Esser,

Egbulefu

et al. 2023

PLoS ONE

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Background Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models. Methods Gene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin. Results TFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60–85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice. Conclusions TfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.

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“…As shown in Figure 4, even a slight change in the structure of the inhibitory compound may lead to a lower inhibitory effect (44)(45)(46). Such correlation was obsevered related to aurintricarboxylic acid (ATA) which reveals high inhibitory effect on PTP1B (47). However, the experiments conducted on other tyrosine phosphatase YopH has shown that the analogs of ATA are weaker inhibitors than their precursor (48).…”

Section: Promising Inhibitors Of Protein Tyrosine Phosphatase Ptp1bmentioning

confidence: 99%

Inhibitors of Protein Tyrosine Phosphatase PTP1B With Anticancer Potential

et al. 2019

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Background/Aim: PTP1B tyrosine phosphatase is involved in the development of many types of cancers, such as breast cancer or lung cancer. Therefore, PTP1B is a promising target for anticancer therapy. The purpose of this review was to present the studies on selected PTP1B inhibitors as a possible treatment and describe the latest trends of current research in this field. Materials and Methods: This literature review was performed using the PubMed database and the analysis of previous research studies of our Department. Results: Recent studies have shown that PTP1B, due to its implication in oncogenic transformation, represents a promising drug target. Conclusion: The selected compounds that are effective PTP1B inhibitors can be considered a promising anticancer treatment, both as monotherapy and in combination with other anticancer drugs. PTP1B Activates Oncogenic Src KinasesPTP1B contributes to oncogenic properties through activation of non-receptor tyrosine kinase Src, which is deregulated in multiple tumor types (11). The crucial role of Src kinases in tumor development is due to their effect on proliferation, survival, adhesion, migration, invasion and metastasis. Src kinase activity has been reported to be elevated in many human cancer cell lines, e.g. breast cancer, lung cancer and 3379

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Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2

Abstract: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.

Cited by 13 publications

References 22 publications

High-Dose Deferoxamine Treatment Disrupts Intracellular Iron Homeostasis, Reduces Growth, and Induces Apoptosis in Metastatic and Nonmetastatic Breast Cancer Cell Lines

High-Dose Deferoxamine Treatment Disrupts Intracellular Iron Homeostasis, Reduces Growth, and Induces Apoptosis in Metastatic and Nonmetastatic Breast Cancer Cell Lines

Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting

Inhibitors of Protein Tyrosine Phosphatase PTP1B With Anticancer Potential

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