Deferoxamine: A Regenerative Therapeutic with Antitumorigenic Potential
Alexis Donneys, MD, Jeremy V. Lynn, N/A, Kevin Urlaub, BS, Kevin Kovatch, MD, Halil Safak Uygur, MD, Jessie Hoxie, N/A, Lauren Buchman, N/A, Kavitha Ranganathan, MD, Alicia Snider, MD, Noah S. Nelson, BS, Chitra Subramanian, PhD, MBA, Mark S. Cohen, MD, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Purpose: The ability of deferoxamine (DFO) to mitigate the deleterious effects of radiation on bone healing and regeneration for head and neck cancer (HNC) reconstruction is currently being investigated. However, there remains concern about the tumorigenic potential of DFO, due to the ability of DFO to induce angiogenesis and promote tissue vascularization. The purpose of this study is to investigate the effects of DFO on head and neck squamous cell carcinoma (HNSCC) in-vitro and in-vivo, to delineate the clinical safety of DFO administration to HNC patients.
Methods: MDA-1986 HNSCC cells were exposed to increasing doses of DFO (0, 25, and 50ÁM) and XRT (0, 5, and 10Gy) in triplicate and counted via hemocytometer to define the dose-dependent effects of each therapy. A 3-D sphere assay was performed to confirm the observed DFO dose response. Subsequently, an MTS assay was performed to comparatively analyze the following groups: control, XRT (5Gy), DFO (100ÁM), and XRT+DFO. Xenograft mouse models were then created in Nu/Nu mice using two million green-luciferase-tagged cells, which were injected SQ to 12 mice. Resulting tumors were allowed 14 days to proliferate. XRT mice received 3 fractionated doses of 3 Gy over the 10-day study. DFO mice received 5 doses of DFO via peritumoral injection. Tumor volumes were measured every third day during treatments. Statistical analysis was performed using ANOVA and paired-t-test, and p=0.05 was considered significant.
Results: In vitro, cell proliferation significantly decreased with increasing doses of XRT. Unexpectedly, DFO also displayed a significant dose-dependent antitumorigenic potency to HNSCC cells when analyzed via hemocytometer. The proceeding DFO-dose response sphere assay confirmed the abovementioned toxicity of DFO. The MTS assay exhibited a significant diminution of cell proliferation in all treatment groups compared to control. Specifically, the addition of DFO reduced cell proliferation to a significantly greater degree than XRT treatment alone, and the combination therapy decreased tumor proliferation significantly more than either single therapy. In vivo, buccal xenografts revealed an increase in control tumor volume by experimental day 6. However, the XRT and DFO groups did not experience a significant increase in tumor volume at any point during the 10-day treatment regimen.
Conclusions: In vitro and in vivo studies reveal DFO exhibits an antitumorigenic effect that is equal to, if not more pronounced than, the potent effects of radiotherapy on HNSCC cell proliferation and tumor formation. Such findings provide preliminary evidence that DFO may be safely utilized in select HNC patient populations to promote new bone formation during head and neck reconstruction following radiotherapy. Moreover, the strong iron-chelating capacity of DFO may offer a promising chemotherapeutic approach to the oncologic management of HNC. Further studies examining the effect of DFO on HNSCC cell subtypes is warranted due to the heterogeneous nature of cancer cell biology.
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