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.

中文翻译：

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DIBI是一种新型的3-羟基吡啶-4-酮螯合剂铁结合聚合物，可抑制乳腺癌细胞的生长，并通过促进S期DNA损伤而起化学增敏剂的作用。

乳腺癌是女性与癌症相关的死亡的主要原因；然而，限制剂量的毒性常常阻碍了乳腺癌的化学疗法，这表明需要使用毒性更小的方法进行治疗。由于乳腺癌细胞的快速生长和代谢导致对铁的需求增加，因此建议使用高选择性铁螯合剂提取生物利用铁代表了一种新的乳腺癌治疗方法。在这里，我们显示了最近开发的铁结合聚合物DIBI抑制了五种不同的乳腺癌细胞系（SK-BR3，MDA-MB-468，MDA-MB-231，MCF-7和T47D）的生长。在对DIBI介导的生长抑制最敏感的MDA-MB-468乳腺癌细胞培养物中，铁撤出与转铁蛋白受体1和铁蛋白H mRNA的表达增加但与铁转运蛋白mRNA的表达减少有关。暴露于DIBI的MDA-MB-468细胞在细胞周期的S期经历了双链DNA断裂。DNA损伤不是由活性氧（ROS）介导的，因为DIBI处理的MDA-MB-468细胞显示出细胞内ROS的减少。DIBI处理的MDA-MB-468细胞还显示出对化疗药物顺铂，阿霉素和4-氢过氧环磷酰胺（环磷酰胺的活性代谢产物）抑制生长的敏感性增加。用DIBI和顺铂联合处理MDA-MB-468细胞会比单独使用任何一种处理引起更大的DNA损伤，这也与凋亡细胞死亡的增加有关。在一起