Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang, 050016, PR China.
Curr Drug Metab. 2010 Jul;11(6):507-15. doi: 10.2174/138920010791636149.
Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxicity, and hemolytic uremic syndrome are often observed at its clinical doses (approximately 60 mg/m(2)), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m(2)/day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of cisplatin and hemosiderin accumulation and iron metabolism in vivo.
顺铂是临床上常用的化疗药物之一，能有效治疗恶性肿瘤，但顺铂在临床剂量（约 60mg/m²）下会产生肾毒性、神经毒性和溶血性尿毒症综合征等不良反应，限制了其更广泛的应用。在早期研究中，人们很少关注低剂量顺铂治疗后淋巴器官结构的细微变化。本文综述了顺铂诱导红细胞损伤的研究现状，并介绍了我们的最新发现，即低剂量顺铂（3.6mg/m²/天，共 14 天）可引起正常和接种肝癌 22 细胞（H22）的 Balb/C 小鼠脾脏中特定的含铁血黄素沉积。该剂量的顺铂可显著抑制 H22 诱导的急性腹水形成。该剂量的顺铂除引起脾脏含铁血黄素沉积外，对正常和荷瘤小鼠的组织无明显毒性。低剂量顺铂处理后，脾脏铁含量增加，红细胞损伤。低剂量顺铂处理后，脾脏铁蛋白和铁蛋白的 mRNA 水平分别上调 25 倍和 5 倍。Western blot 分析也观察到 FPN1 和铁蛋白蛋白的过表达。此外，hepcidin 的 mRNA 表达也增加，表明顺铂处理通过 FPN1 阻断铁在脾脏中的循环。综上所述，顺铂处理破坏了红细胞，这些红细胞在脾脏红髓中积累，FPN1 和铁蛋白蛋白的循环受到损害。hepcidin 抑制 FPN1 的功能作为铁输出蛋白，导致铁蛋白中铁过载，铁蛋白内铁蛋白染色异常。这些结果表明，顺铂引起的脾脏含铁血黄素沉积为理解顺铂毒性和体内含铁血黄素沉积及铁代谢的分子基础提供了有价值的线索。
