Oral deferiprone administration ameliorates cisplatin-induced nephrotoxicity in rats

Makhdoumi, Pouran; Abnous, Khalil; Mehri, Soghra; Etemad, Leila; Imenshahidi, Mohsen; Karimi, Gholamreza

doi:10.1111/jphp.12990

Cited by 16 publications

(7 citation statements)

References 64 publications

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“…We showed that antiferroptotic drugs ameliorated cisplatin-induced AKI and LPS/GalN-induced liver injury. In previous reports, iron chelators prevented lipid peroxidation and ameliorated renal damage in cisplatin nephrotoxicity, 53,54 also suggesting that ferroptosis is involved in the pathophysiology of cisplatin-induced AKI. Although, in this study, the renoprotective effect of Fer-1 was not statistically significant in the cisplatin model (Supplemental Figure 6), recent studies showed that the antiferroptotic effect of Fer-1 is not potent in in vivo conditions, unlike its high activity in vitro, because of its instability in plasma.…”

Section: Discussionmentioning

confidence: 76%

Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

Mishima

Sato

Ito

et al. 2019

JASN

117

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BackgroundFerroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals.MethodsUsing a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury.ResultsWe identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death.ConclusionsAlthough elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

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Section: Discussionmentioning

confidence: 76%

Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

Mishima

Sato

Ito

et al. 2019

JASN

117

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“…It has been reported that the exposure of humans and animals to certain metals or metal-containing compounds leads to toxic and carcinogenic effects like neurotoxicity, hepatoxicity, and nephrotoxicity. , However, several vital transition metals, such as Fe, copper (Cu), zinc, manganese, and cobalt (Co) have an important role in controlling various metabolic and signaling pathways . Since metals have redox properties and rich coordination chemistry, they are capable of moving out of these controlled mechanisms and binding to other compartments, like cell constituents and designated tissue, resulting in the replacement of other metals from their natural binding sites.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Review on Metal-Based Nanoparticles: Role of Reactive Oxygen Species in Renal Toxicity

Makhdoumi

Karimi

Khazaei

2020

Chem. Res. Toxicol.

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The rapidly emerging field of nanotechnology has offered innovative discoveries. Due to a wide variety of nanotechnology applications in the industrial, medical, and consumptive products, the application of nanotechnology has received considerable attention in the past decades. Metal-based nanoparticles including metal and metal oxide nanoparticles are now widely utilized in different areas of nanotechnology, leading to an increase in human exposure to nonmaterial. Since the kidney is one of the major organs to remove a variety of potentially harmful substances, including nanoparticles (NPs), from living organisms and a large proportion of cardiac output reaches the kidney, this organ is susceptible to the toxin-induced renal injury. However, despite the extensive use of NPs, there is still a limited understanding of NP-mediated toxicity. The unique physicochemical properties of metal-based NPs not only make them highly desirable in a variety of applications but also enable them to induce changes at biological levels of cellular activities, including reactive oxygen species (ROS) generation. Since oxidative stress is a key factor of NP-induced injury, it is urgent to characterize the ROS response resulting from metal-based NPs. This review summarizes an assessment of the signaling pathways that are involved in the metal-based NP-induced nephrotoxicity, with a particular focus on ROS production along with the potential oxidative stress-dependent mechanism. However, available data show that metal-based NPs may have a severe impact on the renal system, but the exact molecular mechanism of nephrotoxicity is not fully understood. A highly effective strategy for a better understanding of the mechanism would be to collect an increasing volume of information about the exposure time, physicochemical characteristics of the engineered NPs, and the cellular effects. In order to achieve a thorough knowledge of ROS-dependent renal toxicity, both in vitro and in vivo studies should be considered.

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“…57 Its therapeutic potential, however, is limited by its nephrotoxicity. 58 Ferroptosis has been investigated as a potential mechanism for cisplatin-induced renal injury. 3 Cisplatin treatment augmented the concentration of renal ferrous iron by increasing iron content and expressions of ferritin and transferrin receptor-1 in the kidney of mice.…”

Section: The Role Of Ferroptosis In Cisplatin-induced Nephrotoxicitymentioning

confidence: 99%

The role of ferroptosis in organ toxicity

2021

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Ferroptosis, an iron-dependent form of programmed cell death, is characterized by iron overload, increased reactive oxygen species (ROS) generation, and depletion of glutathione (GSH) and lipid peroxidation. Lipophilic antioxidants and iron chelators can prevent ferroptosis. GSH-dependent glutathione peroxidase 4 (GPX4) prevents lipid ROS accumulation. Ferroptosis is thought to be initiated through GPX4 inactivation. Moreover, mitochondrial iron overload derived from the degradation of ferritin is involved in increasing ROS generation. Ferroptosis has been suggested to explain the mechanism of action of organ toxicity induced by several drugs and chemicals. Inhibition of ferroptosis may provide novel therapeutic opportunities for treatment and even prevention of such organ toxicities.

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Oral deferiprone administration ameliorates cisplatin-induced nephrotoxicity in rats

Abstract: The results supported a role for iron in cisplatin-induced nephrotoxicity and TfR may serve as an important source of iron. Based on these findings, deferiprone pretreatment may play a role in preventing cisplatin-induced nephropathy in cancer patient.

Cited by 16 publications

References 64 publications

Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

Review on Metal-Based Nanoparticles: Role of Reactive Oxygen Species in Renal Toxicity

The role of ferroptosis in organ toxicity

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