Specific Hemosiderin Deposition in Spleen Induced by a Low Dose of Cisplatin: Altered Iron Metabolism and Its Implication as an Acute Hemosiderin Formation Model

Abstract

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, neurotoxcity, and hemolytic uremic syndrome are often observed at its clinical doses (~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.

Cinnamic Acid and Cinnamaldehyde Ameliorate Cisplatin-Induced Splenotoxicity in Rats

“…The reduction of Hb concentration is due to erythrocyte damage induced by CP. These results are in agreement with those obtained by Wang et al who speculated that the splenic injury and hemosiderin deposition might be mainly due to abnormal erythrocyte damage induced by CP. Moreover, our data are consistent with those of Sachs and Lotem and Mazur et al who reported that CP toxicity, at therapeutic doses, to bone marrow cells was evident and probably CP can trigger apoptosis and affect cell cycle causing anemia and a decrease in TLC.…”

Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations

“…Interestingly, brown staining was observed in the spleen from vorinostat or vorinostat and ABT-888 treated mice (panel 'a' in S7 Fig ). It has been noted before that accumulation of hemosiderin in the spleen of cisplatin-treated mice was associated with brown staining in H&E stained preparations [ 34 ]. Indeed Prussian blue staining revealed an increased level of splenic iron in vorinostat or vorinostat and ABT-888 treated mice (panel 'b' in S7 Fig ).…”

Functional Peptide Nanofibers with Unique Tumor Targeting and Enzyme‐Induced Local Retention Properties

“…It is presumed that the liposomal formulation caused damage to erythrocytes, which accelerated their removal by macrophages in the spleen. [37] To assess acute toxicity, we performed hemograms and a blood biochemical analysis for the liver, renal, and muscle parameters in Balb/c mice after the administration of frequent dosages of aldox-NFP, aldox, and Doxil (2.5 mg kg −1 of drug content three times a week). None of the three treatments changed the number and morphology of the blood cells (Figure 8b).…”