Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin
Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin
复制标题
DOI：
10.1016/j.freeradbiomed.2005.03.029
复制
发表时间：
2005-08-01
影响因子：
7.4
通讯作者：
Shacter, E
中科院分区：
文献类型：
--
作者：
Hoke, EM;Maylock, CA;Shacter, E
Desferal是一种临床批准的铁螯合剂，用于治疗铁超载。阿霉素是一种蒽环类抗癌化疗药物，用于治疗乳腺癌。它可以在铁的存在下进行氧化还原循环，产生活性氧。阿霉素的氧化生成活性被认为是该药物的心脏毒性副作用的原因，但尚不清楚它是否也是其抗肿瘤活性所必需的。为了测试铁螯合抗氧化剂是否会干扰多柔比星的肿瘤杀伤活性，将人乳腺癌MDA-MB 231细胞的异种移植物移植到裸鼠上，然后用多柔比星和/或去铁醛处理。去铁胺不仅不干扰阿霉素的抗肿瘤活性，而且它本身就能抑制肿瘤生长。体外研究证实去铁胺抑制乳腺肿瘤生长。然而，它不诱导细胞凋亡，也不诱导细胞周期停滞。相反，去铁素引起细胞停滞，显然是通过铁的消耗。铁饱和转铁蛋白预处理可部分改善去铁醛的细胞生长抑制活性，乳腺癌细胞上转铁蛋白受体表达在去铁醛暴露后几乎翻了一番。与其对肿瘤细胞的作用相反，去铁胺并不抑制正常乳腺上皮细胞的生长。数据表明，阿霉素的抗肿瘤活性不依赖于铁介导的ROS产生。此外，由于去铁醛能够抑制乳腺肿瘤生长和心脏毒性副作用，而不损害蒽环类化疗药物的肿瘤杀伤活性，因此可能具有作为预防性化疗的实用性。爱思唯尔公司出版
Desferal is a clinically approved iron chelator used to treat iron overload. Doxorubicin is an anthracycline cancer chemotherapy drug used in the treatment of breast cancer. It can undergo redox cycling in the presence of iron to produce reactive oxygen species. The oxidant-generating activity of doxorubicin is thought to be responsible for the cardiotoxic side effects of the drug, but it is unclear whether it is also required for its anti-tumor activity. To test whether an iron-chelating antioxidant would interfere with the tumor-killing activity of doxorubicin, nude mice were transplanted with xenografts of human breast cancer MDA-MB 231 cells and then treated with doxorubicin and/or desferal. Not only did desferal not interfere with the anti-tumor activity of doxorubicin, it inhibited tumor growth on its own. In vitro studies confirmed that desferal inhibits breast tumor growth. However, it did not induce apoptosis, nor did it induce cell cycle arrest. Instead, desferal caused cytostasis, apparently through iron depletion. The cytostatic activity of desferal was partially ameliorated by pretreatment with iron-saturated transferrin, and transferrin receptor expression on breast cancer cells nearly doubled after exposure to desferal. In contrast to its effect on tumor cells, desferal did not inhibit growth of normal breast epithelial cells. The data indicate that the anti-tumor activity of doxorubicin is not dependent on iron-mediated ROS production. Furthermore, desferal may have utility as an adjunctive chemotherapy due to its ability to inhibit breast tumor growth and cardiotoxic side effects without compromising the tumor-killing activity of an anthracycline chemotherapy drug. Published by Elsevier Inc.