Power Coombs Melanie R, Grant Taryn, Greenshields Anna L, Arsenault Daniel J, Holbein Bruce E, Hoskin David W
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
Exp Mol Pathol. 2015 Oct;99(2):262-70. doi: 10.1016/j.yexmp.2015.07.008. Epub 2015 Jul 22.
Since iron uptake is essential for cell growth, rapidly dividing cancer cells are sensitive to iron depletion. To explore the effect of iron withdrawal on cancer cell growth, mouse and human mammary carcinoma cells (4T1 and MDA-MB-468, respectively) and mouse and human fibrosarcoma cells (L929 and HT1080, respectively) were cultured in the absence or presence of DIBI, a novel iron-chelating polymer containing hydroxypyridinone iron-ligand functionality. Cell growth was measured by a colorimetric assay for cell metabolic activity. DIBI-treated 4T1, MDA-MB-468, L929 and HT1080 cells, as well as their normal counterparts, showed a dose- and time-dependent reduction in growth that was selective for human cancer cells and mouse fibrosarcoma cells. The inhibitory effect of DIBI on fibrosarcoma and mammary carcinoma cell growth was reversed by addition of exogenous iron in the form of iron (III) citrate, confirming the iron selectivity of DIBI and that its inhibitory activity was iron-related. Fibrosarcoma and mammary carcinoma cell growth inhibition by DIBI was associated with S-phase cell cycle arrest and low to moderate levels of cell death by apoptosis. Consistent with apoptosis induction following DIBI-mediated iron withdrawal, fibrosarcoma and mammary carcinoma cells exhibited mitochondrial membrane permeabilization. A comparison of DIBI to other iron chelators showed that DIBI was superior to deferiprone and similar to or better than deferoxamine for inhibition of fibrosarcoma and mammary carcinoma cell growth. These findings suggest that iron withdrawal from the tumor microenvironment with a selective and potent iron chelator such as DIBI may prevent or inhibit tumor progression.
由于铁摄取对细胞生长至关重要，快速分裂的癌细胞对铁耗竭敏感。为了探究铁去除对癌细胞生长的影响，分别将小鼠和人乳腺癌细胞（分别为4T1和MDA-MB-468）以及小鼠和人纤维肉瘤细胞（分别为L929和HT1080）在不存在或存在DIBI的情况下培养，DIBI是一种含有羟基吡啶酮铁配体功能的新型铁螯合聚合物。通过比色法测定细胞代谢活性来测量细胞生长。经DIBI处理的4T1、MDA-MB-468、L929和HT1080细胞及其正常对应细胞，生长均呈现剂量和时间依赖性降低，且对人癌细胞和小鼠纤维肉瘤细胞具有选择性。通过添加柠檬酸铁（III）形式的外源铁可逆转DIBI对纤维肉瘤和乳腺癌细胞生长的抑制作用，证实了DIBI的铁选择性及其抑制活性与铁相关。DIBI对纤维肉瘤和乳腺癌细胞生长的抑制作用与S期细胞周期停滞以及低至中度水平的凋亡细胞死亡有关。与DIBI介导的铁去除后诱导凋亡一致，纤维肉瘤和乳腺癌细胞表现出线粒体膜通透性增加。将DIBI与其他铁螯合剂进行比较表明，在抑制纤维肉瘤和乳腺癌细胞生长方面，DIBI优于去铁酮，与去铁胺相似或更好。这些发现表明，用选择性且有效的铁螯合剂如DIBI从肿瘤微环境中去除铁可能预防或抑制肿瘤进展。
