Deferoxamine Diminishes Breast Cancer Proliferation and Enhances Irradiated Breast Reconstruction: An Antitumorigenic Mechanism Defined
Jeremy V. Lynn, BS, Kevin M. Urlaub, BS, Kavitha Ranganathan, MD, Alexis Donneys, MD, MS, Noah S. Nelson, MPH, Alexandra O. Luby, MS, Chitra Subramanian, PhD, MBA, Mark S. Cohen, MD, FACS, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Purpose: Radiation plays an essential role in the oncologic management of triple-negative breast cancer, but patients who undergo radiotherapy experience significantly more wound complications during the reconstructive process. Deferoxamine is an FDA-approved iron chelator with immense potential to up-regulate angiogenesis and improve reconstructive outcomes. More specifically, the ability of deferoxamine to mitigate the deleterious effects of radiation on skin and soft tissue has been shown to enhance expander-based irradiated breast reconstruction, increase fat graft retention, and facilitate irradiated transverse rectus abdominis myocutaneous flap survival. The purpose of this study is to determine the impact of deferoxamine on breast cancer cell proliferation in-vitro, in order to delineate oncologic safety concerns regarding the utilization of deferoxamine as a regenerative therapeutic.
Methods: Triple-negative breast cancer cells, which do not respond to hormone or HER2 blocking therapy, were utilized in this study as patients with triple-negative breast cancer commonly receive chemoradiation and are potential candidates to receive deferoxamine as a regenerative therapeutic during the reconstructive process. The effect of radiation and deferoxamine on two triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468) and one female fibroblast control cell line was determined via MTS (percent cell viability) analysis. Radiation (0, 5, 10 Gy) and deferoxamine (0, 25, 50, 75, 100 然) were delivered individually and jointly, and all experiments were completed in triplicate. Intracellular iron concentration was determined via QuantiChromTMassay, NF-κB localization was determined via dual-luciferase reporter assay, and apoptosis/necrosis was determined via annexin V assay in order to delineate mechanism. ANOVA statistical analysis was performed using SPSS (p<0.05).
Results: Both triple-negative breast cancer cell lines exemplified a significant decrease in percent viability following exposure to 10 Gy of radiation (p<0.05) or 25 然 deferoxamine (p<0.01). The administration of radiation (10 Gy) in combination with deferoxamine (100 然) to triple-negative breast cancer cells resulted in significant reduction of percent cell viability compared to the administration of radiation alone (p<0.05). Fibroblasts exemplified no significant response to individually administered radiation (10 Gy) or deferoxamine (100 然), while joint administration of radiation (10Gy) and deferoxamine (25然) resulted in a significant increase in percent cell viability compared to the administration of radiation alone (p<0.05). In both triple-negative breast cancer cell lines, individual administration of deferoxamine (100然) significantly decreased intracellular iron concentration (p<0.05). Joint administration of radiation and deferoxamine suppressed NF-κB activation indicating a cessation of cell proliferation and amplified cellular apoptosis (p<0.01) with no notable increase in cellular necrosis.
Conclusions: The administration of radiation and/or deferoxamine imparts a significant decrease in triple-negative breast cancer cell proliferation, without significantly impeding growth of female fibroblast control cells in-vitro. Mechanistically, deferoxamine administration decreases intracellular iron concentration leading to decreased cell proliferation and increased cell death via apoptosis. Taken together, these findings suggest deferoxamine may be safely utilized to facilitate improved reconstructive outcomes among triple-negative breast cancer survivors and warrant future investigations to quantify in-vivoeffects.
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