Effect of Cisplatin on Renal Iron Homeostasis Components: Implication in Nephropathy

Abstract

Cisplatin is an important chemotherapeutic drug for the treatment of solid tumors but often causes nephropathy as part of the off-target toxicity. Iron accumulation and related damage were implicated in cisplatin-induced kidney injury. However, the role of cisplatin in the renal iron sensing mechanism and its target genes responsible for iron uptake, storage, and release have not been investigated. Cellular iron homeostasis is controlled by the interaction of iron regulatory proteins (IRP1 and IRP2) and iron-responsive elements (IREs) present in the untranslated regions of iron transport and storage components. Here, we report that cisplatin does not influence the expressions of IRP targets such as transferrin receptor-1 (TfR1), divalent metal transporter-1 (DMT1), and ferroportin in renal cells despite the increased heme oxygenase-1 (HO-1) level. Ferritin subunits (Ft-H and Ft-L) are elevated in different magnitudes due to the increased mRNA expression. Intriguingly, a higher expression of Ft-L mRNA is detected than that of Ft-H mRNA. The inability of cisplatin in altering the IRE–IRP interaction is confirmed by examining IRE-containing luciferase activity, RNA electrophoretic mobility shift assay, and activation of IRPs. The labile iron pool is depleted but reversed by silencing of either Ft-H or Ft-L, suggesting increased iron storage by ferritin. Silencing of Ft-H or Ft-L promotes cell death, suggesting that ferritin acts to protect the renal cells from cisplatin-mediated toxicity. A differential increase of transcripts and equivalent increase of proteins of Ft-H and Ft-L and unaltered TfR1 and DMT1 transcripts are found in the kidneys of cisplatin-treated rats along with iron accumulation. Our results reveal that cisplatin does not influence the IRE–IRP interaction despite alteration of the cellular iron pool in renal cells. This insensitivity of the IRE–IRP system may be implicated in the accumulation of iron to contribute to cisplatin-induced nephropathy.

The Role of Cdo1 in Ferroptosis and Apoptosis in Cancer

“…These drugs can lead to an off-target effect. Cisplatin promotes ferroptosis by inhibiting GPX4, and its off-target effect is mainly reflected in its nephrotoxicity [55][56][57]. Sorafenib induces ferroptosis by increasing intracellular iron levels and inhibiting the cystine/glutamate antiporter, and its off-target effect is mainly due to skin toxicity and causes diarrhea and arterial hypertension in patients [55,57,58].…”

“…Cisplatin promotes ferroptosis by inhibiting GPX4, and its off-target effect is mainly reflected in its nephrotoxicity [55][56][57]. Sorafenib induces ferroptosis by increasing intracellular iron levels and inhibiting the cystine/glutamate antiporter, and its off-target effect is mainly due to skin toxicity and causes diarrhea and arterial hypertension in patients [55,57,58]. Statin induces ferroptosis mainly by inhibiting two protective pathways containing GPX4 and FSP1, and its off-target effect is mainly to increase the Hemorrhagic Stroke Risk, as well as the myopathic effect [55,57,59].…”

“…mainly by inhibiting two protective pathways containing GPX4 and FSP1, and its off-target effect is mainly to increase the Hemorrhagic Stroke Risk, as well as the myopathic effect [55,57,59].…”

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

“…In contrast, the kidney is the major target organ of toxicity for cisplatin, an anticancer drug widely used for the treatment of about 50% of patients with different cancer categories [ 252 , 253 ]. In this case, labile iron and hemosiderin iron accumulation were implicated and suspected to play a role in the cisplatin-induced kidney injury [ 62 , 254 , 255 , 256 ]. The enhancement of iron-induced free radical toxicity has also been observed by the chelating drug EDTA, with some investigators questioning its safety in alternative medicine ( Figure 2 ) [ 257 , 258 ].…”