Abstract
Breast cancer is a leading cause of cancer-related death in women; however, chemotherapy of breast cancer is often hindered by dose-limiting toxicities, demonstrating the need for less toxic approaches to treatment. Since the rapid growth and metabolism of breast cancer cells results in an increased requirement for iron, withdrawal of bioavailable iron using highly selective iron chelators has been suggested to represent a new approach to breast cancer treatment. Here we show that the recently developed iron-binding polymer DIBI inhibited the growth of five different breast cancer cell lines (SK-BR3, MDA-MB-468, MDA-MB-231, MCF-7, and T47D). In cultures of MDA-MB-468 breast cancer cells, which were most sensitive to DIBI-mediated growth inhibition, iron withdrawal was associated with increased expression of transferrin receptor 1 and ferritin H mRNA but decreased expression of ferroportin mRNA. MDA-MB-468 cells that were exposed to DIBI experienced double-strand DNA breaks during the S phase of the cell cycle. DNA damage was not mediated by reactive oxygen species (ROS) since DIBI-treated MDA-MB-468 cells exhibited a reduction in intracellular ROS. DIBI-treated MDA-MB-468 cells also showed increased sensitivity to growth inhibition by the chemotherapeutic drugs cisplatin, doxorubicin, and 4-hydroperoxy cyclophosphamide (active metabolite of cyclophosphamide). Combination treatment of MDA-MB-468 cells with DIBI and cisplatin caused greater DNA damage than either treatment alone, which was also associated with an increase in apoptotic cell death. Taken together, these findings suggest that DIBI-mediated iron withdrawal may enhance the effect of chemotherapeutic agents used in breast cancer treatment.
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Acknowledgements
This work was supported by an Engage Grant from the Natural Sciences Engineering Research Council of Canada and a Productivity and Innovation Voucher from the Nova Scotia Economic and Rural Development and Tourism. Melanie Coombs and Anna Greenshields are recipients of Mitacs Accelerate and Elevate Awards, respectively. The authors thank Chelation Partners Inc. for financial support with Mitacs and for supplying the DIBI iron chelator. We are grateful for helpful advice provided to us by Dr. Trisha Ang.
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BE. Holbein has a beneficial interest in Chelation Partners Inc. The other authors declare that there are no conflicts of interest.
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Greenshields, A.L., Power Coombs, M.R., Fernando, W. et al. DIBI, a novel 3-hydroxypyridin-4-one chelator iron-binding polymer, inhibits breast cancer cell growth and functions as a chemosensitizer by promoting S-phase DNA damage. Biometals 32, 909–921 (2019). https://doi.org/10.1007/s10534-019-00222-3
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DOI: https://doi.org/10.1007/s10534-019-00222-3