Journal
THERANOSTICS
Volume 11, Issue 7, Pages 3167-3182Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.52028
Keywords
Holo-Lf; ferroptosis; radiotherapy; triple-negative breast cancer; hypoxia
Categories
Funding
- National Natural Science Foundation of China [81973024, 82073482]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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The study showed that iron-saturated Lactoferrin (Holo-Lf) can induce ferroptosis in triple-negative breast cancer cells and enhance their sensitivity to radiotherapy. Conversely, low iron-saturated Lactoferrin (Apo-Lf) may inhibit this cell death process. Non-triple-negative breast cancer cells may have resistance to Holo-Lf-induced ferroptosis due to higher redox balance capacity.
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 alpha 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.
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