Dataset Information

Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer.

ABSTRACT: Rationale: Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. Methods: The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell line MDA-MB-231 and non-TNBC cell line MCF-7. Results: Holo-Lf significantly increased the total iron content, promoted ROS generation, increased lipid peroxidation end product, malondialdehyde (MDA), and enhanced ferroptosis of MDA-MB-231 cells. By contrast, Apo-Lf upregulated SLC7a11 expression, increased GSH generation and inhibited ferroptosis of MDA-MB-231 cells. However, non-TNBC MCF-7 cells were resistant to Holo-Lf-induced ferroptosis because MCF-7 cells have a higher redox balance capacity than MDA-MB-231 cells. More importantly, Holo-Lf downregulated HIF-1? expression, ameliorated the hypoxia microenvironment in subcutaneous MDA-MB-231 tumors, and promoted radiation-induced DNA damage to hypoxic MDA-MB-231 cells. Finally, the efficacy of radiotherapy to MDA-MB-231 tumors was enhanced by Holo-Lf. Conclusion: Holo-Lf could induce ferroptosis in MDA-MB-231 cells and sensitize MDA-MB-231 tumors to radiotherapy.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7847686 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer.

Zhang Zheng Z Lu Menglan M Chen Cailong C Tong Xing X Li Yunhong Y Yang Kai K Lv Haitao H Xu Jiaying J Qin Liqiang L

Theranostics 20210101 7

<b>Rationale:</b> Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. <b>Methods:</b> The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell ...[more]

PMID: 33537080

Similar Datasets

Project description:The so called "Triple Negative Breast Cancer" (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC. In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new "clever drugs" able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients. A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients. In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the need for a completely different type of clinical trials.

Project description:PURPOSE:Auger electrons emitted by radioisotopes such as 125I have a high linear energy transfer and short mean-free path in tissue (<10??m), making them suitable for treating micrometastases while sparing normal tissues. The authors developed and subsequently investigated a cancer cell-selective small molecule phospholipid ether analog to deliver 125I to triple-negative breast cancer (TNBC) cells in vivo. METHODS:A Current Good Manufacturing Practice (cGMP) method to radiolabel 125I-CLR1404 (CLR 125) with >95% radiochemical purity was established. To estimate CLR 125 in vivo dosimetry and identify dose-limiting organs, the biodistribution of the analog compound 124I-CLR1404 (CLR 124) was investigated using micro-positron emission tomography (PET)/computed tomography (CT) in conjunction with a Monte Carlo dosimetry platform to estimate CLR 125 dosimetry. In vivo antitumor efficacy was tested by injecting nude mice bearing either MDA-MB-231-luc orthotopic xenografts or lung metastases with 74?MBq (3.7 GBq/kg) of CLR 125 or an equivalent mass amount of nonradiolabeled CLR 125. Longitudinal tumor measurements using calipers and bioluminescence imaging were obtained for the xenografts and lung metastases, respectively. RESULTS:Dosimetry analysis estimated that CLR 125 would impart the largest absorbed dose to the tumor per injected activity (0.261?±?0.023 Gy/MBq) while the bone marrow, which is generally the dose-limiting organ for CLR1404, appears to have the lowest (0.063?±?0.005 Gy/MBq). At administered activities of up to 74?MBq (3.7 GBq/kg), mice did not experience signs of toxicity. In addition, a single dose of CLR 125 reduced the volume of orthotopic primary TNBC xenografts by ?60% compared to control vehicle (p?<?0.001) and significantly extended survival. In addition, CLR 125 was efficacious against preclinical metastatic TNBC models by inhibiting the progression of micrometastases (p?<?0.01). CONCLUSIONS:Targeted radionuclide therapy with CLR 125 displayed significant antitumor efficacy in vivo, suggesting promise for treatment of TNBC micrometastases.

Dataset Information

Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer.

Publications

Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure