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Full-Text.Pdf BASIC RESEARCH www.jasn.org Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers Eikan Mishima ,1 Emiko Sato,1,2 Junya Ito,3 Ken-ichi Yamada,4 Chitose Suzuki,1 Yoshitsugu Oikawa,5 Tetsuro Matsuhashi,5 Koichi Kikuchi,1 Takafumi Toyohara,1 Takehiro Suzuki,1 Sadayoshi Ito,1,6 Kiyotaka Nakagawa,3 and Takaaki Abe 1,7,8 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Ferroptosis, 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 iden- tified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mecha- nisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals. Methods Using 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. Results We identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, pro- pranolol, 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 ele- vated 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. Conclusions Although elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI. JASN 31: ccc–ccc, 2019. doi: https://doi.org/10.1681/ASN.2019060570 Ferroptosis is an iron-dependent nonapoptotic reg- reported.4–6 Among renal disorders and diseases, ulated cell death characterized by extensive lipid ferroptosis has been reported to contribute to the peroxide accumulation, which is induced by dis- rupting the glutathione-dependent lipid peroxide defense system.1,2 Emerging evidence implicates Received June 6, 2019. Accepted October 17, 2019. ferroptosis in various disorders, including acute or- Published online ahead of print. Publication date available at gan injury and neurodegenerative diseases, www.jasn.org. and in a cellular mechanism that promotes tumor Correspondence: Dr. Eikan Mishima, Division of Nephrology, suppression.3 The pathophysiologic importance of Endocrinology and Vascular Medicine, Tohoku University, Sendai, ferroptosis in stroke, myocardial infarction, and Miyagi, Japan. Email: [email protected] post-transplant immune response has also been Copyright © 2019 by the American Society of Nephrology JASN 31: ccc–ccc,2019 ISSN : 1046-6673/3102-ccc 1 BASIC RESEARCH www.jasn.org pathophysiology in AKI, ischemia-reperfusion damage, dru- Significance Statement g-induced kidney injury, rhabdomyolysis-associated renal damage, and growth of renal cysts.7–11 Thus, a better under- Ferroptosis, cell death mediated by free radical reactions and standing of ferroptosis and the development of an effective driven by oxidative degradation of lipids, is a therapeutic target intervention could lead to therapies for these disorders. because of its role in organ injuries, including AKI. However, the ferroptosis-causing radicals targeted by ferroptosis suppressors Ferroptosis onset can be prevented by lipid peroxidation have not been unequivocally identified. Certain cytochrome P450 suppression, indicating that this form of cell death is pharma- substrate drugs are known to prevent lipid peroxidation via obscure cologically accessible. Because lipid peroxidation is mediated mechanisms. The authors screened cytochrome P450 substrate by nonenzymatic radical reactions or enzymatic lipoxygenase drugs, identifying a diverse group of drugs with antiferroptotic (LOX) activity in the presence of iron,12 radical-trapping properties, including promethazine and rifampicin. The anti- ferroptotic effect of these drugs was linked to their scavenging agents, LOX inhibitors, and iron chelators prevent ferroptosis activity against lipid peroxyl radicals. Elevated lipid peroxyl radical by blocking lipid peroxidation.3 In addition to known ferrop- levels were associated with ferroptosis onset, whereas radical tosis suppressors such as the lipophilic antioxidants ferrosta- scavenging by the drugs suppressed ferroptosis-related pathologic tin-1 (Fer-1) and liproxstatin-1, several other antioxidant changes in different renal cell types and ameliorated organ injuries compounds have been reported to exert antiferroptotic ef- (including AKI) in mice, suggesting therapeutic potential for such repurposed drugs. fects,13–15 suggesting the involvement of reactive oxygen species (ROS) in ferroptosis. However, the key radical species that are targeted by ferroptosis suppressors have not been mechanisms are not well understood.25–27 We hypothesized unequivocally identified. that these CYP substrate types might prevent ferroptosis by Lipid peroxidation is propagated by a chain reaction of lipid blocking lipid peroxidation and proposed that the elucidation peroxyl radicals.16 During the nonenzymatic step of lipid per- of the antiferroptotic mechanisms of these drugs may help to oxidation initiation, a lipid radical reacts with oxygen to form determine the causative radicals and activities associated with the lipid peroxyl radical, which can generate a lipid hydroper- ferroptosis onset. In this study, we tested CYP substrates to oxide and another lipid radical, leading to a chain reaction. identify drugs with antiferroptotic properties. To investigate In the LOX pathway, a polyunsaturated fatty acid is converted the mechanism, utilizing NBD-Pen and the ESR–spin trapping into lipid hydroperoxide, which is decomposed to a lipid per- method, we examined the radical-scavenging activity of the oxyl radical to initiate the chain reaction. Thus, scavenging potential antiferroptotic drugs especially toward lipid peroxyl lipid peroxyl radicals could stop the radical chain reaction, radicals. In addition, we evaluated the therapeutic potency of which would prevent ferroptosis. It has been proposed the drugs in organ injury models of mice including AKI. Our that the mechanism of the antiferroptotic effect of the radi- findings suggested that the elevated lipid peroxyl radical levels cal-trapping agents is on the basis of their scavenging activity were associated with ferroptosis onset, whereas scavenging toward lipid ROS.17 However, evidence for their lipid ROS lipid peroxyl radicals by the drugs suppressed ferroptosis- scavenger activity has been insufficient because of the techni- related pathologic conditions. cal difficulties associated with performing direct measure- ments of lipid radicals. Although antioxidative activities of Fer-1 and liproxstatin-1 have been evaluated by standard METHODS assays measuring 2,2-diphenyl-1-picrylhydrazyl reduction ac- tivity and suppression of C11-BODIPY581/591 oxidation,14,18 Detailed methods are shown in the Supplemental Material. these methods did not directly demonstrate scavenging ac- tivity toward lipid radicals. The only currently established Cell Lines method to monitor lipid radicals uses electron spin reso- H9C2 (rat cardiomyoblast), NRK49F (rat kidney fibroblast), nance (ESR)–spin trapping techniques,19 but we recently HK2 (human kidney tubular cell), C2C12 (mouse myoblast), developed a specific fluorescence probe for lipid radicals, MDA-MB-231 (human breast adenocarcinoma), NRK52E 2,2,6-trimethyl-4-(4-nitrobenzo[1,2,5]oxadiazol-7-ylamino)- (rat kidney tubular cell), and LLC-PK1 (porcine kidney tubu- 6-pentylpiperidine-1-oxyl (NBD-Pen), which enabled us to lar cell) cells were obtained from ATCC. Panc-1 (human pan- directly detect lipid-derived radicals with high sensitivity and creas carcinoma) cells were obtained from the Cell Resource selectivity.20 Center for Biomedical Research, Tohoku University (Sendai, Cytochrome P450 families (CYP) contain key enzymes of Japan). HT-22 cells were purchased from Millipore. Human drug metabolism and steroid hormone synthesis that can also urine-derived podocyte-like epithelial cells (HUPECs) were convert lipophilic substrates to hydrophilic products.21 Some provided by Dr. Jeffrey B. Kopp (National Institutes of Health, CYP-catalyzed reactions are involved in ROS production and Bethesda, MD).28 AllcelllinesexceptHUPECweremain- lipid peroxidation.12,22 Earlier in vitro studies on microsomes tained in DMEM high glucose (4.5 g glucose/L) supplemented demonstrated that certain CYP substrates and CYP-inducing with 10% FBS,
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