process to promote ferroptosis. Kitakata H, Endo J, Matsushima H, Yamamoto S, Ikura H, Hirai A et al. Ferroptosis is initiated by the loss of GPX4 activity, which is mediated by two distinct mechanisms (Figure Figure1 1).The first mechanism is the inhibition of system Xc-(e.g., mediated by erastin), which indirectly inhibits GPX4 (Dixon et al., 2012, 2014).System Xc-is a cystine/glutamate antiporter that imports extracellular cystine in exchange for intracellular . erefore, induction of 3 ferroptosis has become a novel potential therapeutic strategy for cancer therapy [7-12]. Recent progress in ferroptosis inducers for cancer therapy. System Xc− (a cystine/glutamate antiporter system) is a . The effect of ferrostatin-1 appears to be superior to agents that inhibit other RCD . Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui. Doxorubicin hydrochloride. Breast cancer is the most commonly being diagnosed AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in . Doxorubicin Vincristine: Transfection efficiency 70-80% Reduced mRNA levels of MDR1 Reduced P-gp expression Enhanced cytotoxicity of doxorubicin : Magnetic nanovector - Chlorotoxin: 111.9 nm +19.6 mV - Enhanced specificity via chlorotoxin modification Receptor-mediated cellular internalization Increased gene silencing : Chitosan-TPP . This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. Therefore, we used Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy. roptosis and ferroptosis in melanoma cells (31). However, the significance of MITOL in cardiomyocytes under physiological and pathological conditions remains unclear.First, to determine the significance of MITOL in unstressed hearts, we assessed the cellular changes with the reduction of MITOL expression by siRNA in neonatal . Journal of Molecular and Cellular Cardiology . Cell Death Dis 11, 756 (2020). Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. View Article: Google Scholar: PubMed/NCBI. Mechanisms of Ferroptosis. Emerging strategies of cancer therapy based on . This research, therefore, explores the role and mechanism of DXZ in DOX-induced ferroptosis and cardiomyopathy in rats. In the heart, ablation of parkin rescued the cardiac phenotype of DRP1-homozygous knockout mice, suggesting that Inducing ferroptosis has been acknowledged as an emerging strategy to kill drug-resistant tumor cells, but how to efficiently induce ferroptosis at the tumor site and enhance its therapeutic efficacy are still highly challenging. Kai Hou, Jianliang Shen, Junrong Yan, Chuannan Zhai, Jingxia Zhang, Ji An Pan, Ye Zhang, Yaping Jiang, Yongbo Wang, Richard Z. Lin, Hongliang Cong, Shenglan Gao, Wei Xing Zong. Abstract. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from . Cancer cells tend to modulate their redox state to prevent excessive peroxidation, eventually facilitating tumor growth. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. Small molecule ferroptosis inducers had a strong inhibition of tumor growth and enhanced the sensitivity of chemotherapeutic drugs . Ferrostatins, liproxstatins and many other inhibitors of ferroptosis have been shown to protect the liver, kidney [ 15 ], brain [ 19 ] and heart [ 20 ] in mouse models of ischemic injury. Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin. Specific inhibitors of ferroptosis, such as ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), were identified, and these inhibitors act as radical-trapping antioxidants (RTAs) specifically . Doxorubicin-induced cardiomyopathy correlated with decreased expression of GPx4 and increased lipid peroxidation, leading to ferroptosis and functional impairment of the left ventricular ejection . the FoxO4/ENPP2 axis and ferroptosis may provide potential therapies for alleviating DOX‑induced cardiotoxicity. Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. DOX-induced mitochondrial dysfunction, which causes reactive oxygen species (ROS) generation, cardiomyocyte death, bioenergetic failure, and decreased cardiac function, is a very important mechanism of cardiotoxicity. PDF. Abstract. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity Tomonori Tadokoro , 1 Masataka Ikeda , 1 Tomomi Ide , 2 Hiroko Deguchi , 1 Soichiro Ikeda , 1 Kosuke Okabe , 1 Akihito Ishikita , 1 Shouji Matsushima , 3 Tomoko Koumura , 4 Ken-ichi Yamada , 5 Hirotaka Imai , 4 and Hiroyuki Tsutsui 1 Ferrostatins, liproxstatins and many other inhibitors of ferroptosis have been shown to protect the liver, kidney [15], brain [19] and heart [20] in mouse models of ischemic injury. Moreover, doxorubicin is an FDA-approved anticancer drug capable of inhibiting topoisomerase 2 in tumor cells to prevent DNA replication, leading to a Ferroptosis Drives DOX-Induced Cardiomyopathy and Mortality in Mice. Ferroptosis is a newly identified iron-dependent programmed cell death, which is distinct from apoptosis, autophagy, necroptosis and pyroptosis. table Fe-doxorubicin preloaded amorphous CaCO 3 nanoformula-tion triggers ferroptosis in target tumor cells. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. Ferroptosis, another pathway by which doxorubicin exerts its cardiotoxic effect, is an RCD pathway characterized by the iron-dependent accumulation of lipid peroxides 39. However, the significance of MITOL in cardiomyocytes under physiological and pathological conditions remains unclear. Doxorubicin (DOX)-induced ferroptosis in cardiomyocytes causes distortion and enlargement of the myocardial mitochondria [18]. Ferroptosis is distinct from apoptosis, necroptosis, autophagy, and other types of cell death in morphology and function. Topoisomerase ADC Cytotoxin AMPK Autophagy Apoptosis HIV HBV Mitophagy Antibiotic Bacterial Cancer Infection; Doxorubicin (Hydroxydaunorubicin) hydrochloride, a cytotoxic anthracycline antibiotic, is an anti-cancer chemotherapy agent.Doxorubicin hydrochloride is a potent human DNA topoisomerase I and topoisomerase II inhibitor with . Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. Hydroxydaunorubicin hydrochloride. Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). Ferroptosis. Doxorubicin (DOX)-induced ferroptosis in cardiomyocytes causes distortion and enlargement of the myocardial mitochondria . This novel cell death modality has been implicated in preventing cancer progression. 11:7562020. The cytotoxic effects on tumor cells for DOX were exerted mainly by Runlin Yang†, Yaoqi Li†, Xinyu Wang *, Junjie Yan, Donghui Pan, Yuping Xu, Lizhen Wang and Min Yang * Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China. Doxorubicin-induced accumulation of ROS and lipid peroxidation can lead to cardiomyocyte ferroptosis (Koleini et al., 2019). Doxorubicin-induced cardiomyopathy and ferroptosis are suppressed in TRIM21 À/À hearts. (II)-based liposomal nanosystem, which simultaneously encapsulates doxorubicin hydrochloride (DOX), for . Activation of TLR 4 and NOX 4 has also been proven to promote DOX-induced cardiomyocyte ferroptosis (Chen et al., 2019). Though both are deemed crucial in the progression of DIC, loss of myocyte could be more important as it is an irreversible process and generates a poorer prognosis, even fatal . DOX showed powerful therapeutic effects on a wide range of cancer,10 including acute leukemia, lymphoma, breast cancer, and lung cancer. Mice administered doxorubicin and ferrostatin-1, a ferroptosis inhibitor, have improved survival 52,53 . Doxorubicin (DOX) is a potent anthracycline that Ferroptosis is an iron-dependent cell death, which is characterized by iron overload and lipid peroxidation. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. Doxorubicin (DOX) is one of anti-tumor chemotherapeutic drugs, which have been used in clinical. Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition. MITOL/MARCH5 is an E3 ubiquitin ligase that plays a crucial role in the control of mitochondrial quality and function. Moreover, doxorubicin is an FDA-approved anticancer drug capable of inhibiting topoisomerase 2 in tumor cells to prevent DNA replication, leading to a complementary ferroptosis/apoptosis effect . Herein, a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin (DOX), iron and unsaturated lipid for efficient ferroptosis. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. Runlin Yang†, Yaoqi Li†, Xinyu Wang *, Junjie Yan, Donghui Pan, Yuping Xu, Lizhen Wang and Min Yang * Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China. Ferroptosis is a type of oxidative stress-dependent regulated necrosis characterized by excessive lipid peroxide accumulation. 1A).Our analysis revealed that the ferroptosis inhibitor Fer-1 significantly reduced . Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Sci Adv, 2020, 6: eaax1346 5 Liang C, Zhang X, Yang M, et al. Doxorubicin loaded ferritin nanoparticles for ferroptosis enhanced targeted killing of cancer cells. Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the . ferroptosis in many diseases, such as leukemia (20), acute liver failure (21), and diabetic nephropathy (22). The Mitochondrial Permeability Transition Pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. Ferroptosis is a form of regulated cell death with clinical translational potential, but the efficacy of ferroptosis-inducing agents is susceptible to many endogenous factors when administe … Tumor microenvironment-activatable Fe-doxorubicin preloaded amorphous CaCO 3 nanoformulation triggers ferroptosis in target tumor cells tmozolomide, cisplatin, doxorubicin with ferroptosis inducer erastin resulted in a remarkable synergistic eect on tumor treatment []. In this work, PDA NPs were loaded with Fe3+ at different pH . Ferroptosis is regulated by a variety of factors and controlled by several mechanisms, including mitochondrial activity and metabolism of iron, lipid, and amino acids. Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). The nanoplatform was simultaneously modified by dendrimers with metalloproteinase-2 (MMP-2 . Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity Tomonori Tadokoro, 1 Masataka Ikeda, 1 Tomomi Ide, 2 Hiroko Deguchi, 1 Soichiro Ikeda, 1 Kosuke Okabe, 1 Akihito Ishikita, 1 Shouji Matsushima, 3 Tomoko Koumura, 4 Ken-ichi Yamada, 5 Hirotaka Imai, 4 and Hiroyuki Tsutsui 1 First, to determine the significance of MITOL in unstressed hea … Liu, Y., Zeng, L., Yang, Y. et al. Read more related scholarly scientific articles and abstracts. In conclusion, the data indicated that ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from DOX‑induced toxicity by inhibiting ferroptosis. Kaplan-Meier survival analysis was performed in rats treated by DOX in combination with ferroptosis inhibitor (FER-1) or . First, to investigate the relative contributions of various forms of cell death in DOX-induced cardiotoxicity, we measured survival following a single dose of DOX in mice in the absence or presence of various inhibitors of cell death (Fig. Moreover, doxorubicin is an FDA-approved anticancer drug capable of inhibiting the topoisomerase 2 in tumor cells to prevent DNA replication, leading to complementary ferroptosis/apoptosis effect against a broad spectrum of tumor indications." Moreover, doxorubicin is an FDA-approved anticancer drug capable of inhibiting the topoisomerase 2 in tumor cells to prevent DNA replication, leading to complementary ferroptosis/apoptosis effect against a broad spectrum of tumor indications." The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin . ferroptosis. Therefore, specific treatment approaches targeting the FoxO4/ENPP2 axis and ferroptosis may provide potential therapies for alleviating DOX‑induced cardiotoxicity. Mounting evidence suggests ferroptosis plays a pathogenic role in a plethora of human diseases, such as tissue injuries, Liu Y, Zeng L, Yang Y, Chen C, Wang D and Wang H: Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition. Ferroptosis is gaining followers as mechanism of selective killing cancer cells in a non-apoptotic manner, and novel nanosystems capable of inducing this iron-dependent death are being increasingly developed. (a) Relative TRIM21 expression in human heart tissue samples under indicated conditions. 6 Epigallocatechin-3-gallate pretreatment alleviates doxorubicin-induced ferroptosis and cardiotoxicity by upregulating AMPKα2 and activating adaptive autophagy. Text. Doxorubicin (Dox) is a potent chemotherapeutic agent widely used to treat a variety of cancers, including leuke- . Ferroptosis, a form of cell death that is initiated by iron-dependent lipid peroxidation of the cell membrane, is associated with cellular antioxidant capacity and has been reported to be induced by doxorubicin, hence is a potential target for protection against doxorubicin-induced cardiotoxicity [24,27]. Doxorubicin (DOX) is an anticancer drug widely used in cancer . The effect of ferrostatin-1 appears to be superior to agents that inhibit other RCD . The influence of DOX on the Ca 2+ -induced MPTP opening in the presence of iron has not yet been studied. Ferroptosis is a new mode of cell death, which can be induced by Fenton reaction-mediated lipid peroxidation. Cell Death Dis. DOX is an effective and widely used antitumor drug. MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis. Introduction. Among them, polydopamine nanoparticles (PDA NPs) are arousing interest, since they have great capability of chelating iron. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. icity [22-26]. Doxorubicin (DOXO) induced-cardiotoxicity is a well-known adverse event in cancer patients [1, 2].As recently described in literature, DOXO-induced cardiotoxicity involves pro-inflammatory interleukins, pro-oxidative markers, ferroptosis, topoisomerase IIβ inhibition and mitochondrial dysfunction [3,4,5].Improvement in knowledge of DOXO-induced pathophysiology pushes the search for new . Epigallocatechin-3-gallate pretreatment alleviates doxorubicin-induced ferroptosis and cardiotoxicity by upregulating AMPKα2 and activating adaptive autophagy Huan He , a, c Liang Wang , b Yang Qiao , c Bin Yang , c Dong Yin , d, ∗∗ and Ming He a, c, ∗ Ferroptosis and Doxorubicin-Induced Cardiomyopathy There are two main classifications for DOX-induced myocardial injuries: contractile dysfunction and loss of myocyte. MITOL/MARCH5 is an E3 ubiquitin ligase that plays a crucial role in the control of mitochondrial quality and function. Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition Cell Death Dis. Huan He, Liang Wang and 4 more Open Access December 31, 2021 A locked padlock) or https:// means you've safely connected to the .gov website. These cellular processes are . However, the insufficient H 2 O 2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis. The concept of ferroptosis was first proposed in 2012 [].Ferroptosis is a distinct form of cell death that differs from typical apoptosis, autophagy, and other programmed cell deaths, and is characterized by iron-dependent lipid-based reactive oxygen species accumulation [].In addition, mitochondrial morphology undergoes obvious changes during ferroptosis, including mitochondrial shrinkage . MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis Author links open overlay panel Hiroki Kitakata a Jin Endo a Hirokazu Matsushima a Shoichi Yamamoto a Hidehiko Ikura a Akeo Hirai a Seien Koh a Genki Ichihara a Takahiro Hiraide a Hidenori Moriyama a Kohsuke Shirakawa a . However, mechanisms of cardiomyocyte death remain unclear. Doxorubicin promotes the degradation of heme and increases the level of intracellular free Fe 2+, leading to mitochondrial iron overload. https . Here, we report an amorphous calcium carbonate (ACC)-based nanoassembly for tumor-targeted ferroptosis therapy, in which the totally degradable ACC substrate could synergize with the therapeutic interaction between doxorubicin (DOX) and Fe 2+. Methods: The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. The involvement of ferroptosis in chemotherapyinduced cardiomyopathy, is confirmed by transgenic mouse models in which sequestration of Keap1 grants cardiac protection from doxorubicin-induced . Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). Most interestingly, doxorubicin cytotoxicity on myocytes can be decreased through inhibition of ferroptosis induced by over expression of GPX4 and activation of Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 signalling . Adv Mater, 2019, 31: 1904197 6 Shen Z, Song J, Yung BC, et al. Share sensitive information only on official, secure websites. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin . Doxorubicin loaded ferritin nanoparticles for ferroptosis enhanced targeted killing of cancer cells. by Yunchang Liu, Liping Zeng, Yong Yang, Chen Chen, Daowen Wang, Hong Wang. PDF. The involvement of ferroptosis in chemotherapyinduced cardiomyopathy, is confirmed by transgenic mouse models in which sequestration of Keap1 grants cardiac protection from doxorubicin-induced . Text. On the other hand, doxorubicin can also inhibit the level of GPX4 in mitochondria, enhancing the lipid peroxidation on mitochondrial membrane. Cell death & disease. Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. However, clinical application of this medication is limited due to its cumulative and irreversible cardiotoxicity. Doxorubicin-induced ferroptosis in cardiomyocytes. However, its clinical use is hampered by its cardiotoxicity. A new strategy to trigger ferroptosis in target cancer cells using drug-metal coordination complexes -Doxorubicin and ferrous ions could form acid-dissociable coordination complexes, which were incorporated into functionally tailored amorphous calcium carbonate nanoparticles and may confer severe ferroptotic damage to target tumor cells, published on Sci Ferroptosis was first proposed by Dixon as a novel cell death in 2012 [].Unlike autophagy and apoptosis, ferroptosis is an iron-dependent and reactive oxygen species (ROS)-reliant cell death with characteristics mainly of cytological changes, including decreased or vanished mitochondria cristae, a ruptured outer mitochondrial membrane, and a condensed mitochondrial membrane [2,3,4,5,6]. Introduction Cardiovascular complications due to cancer therapy cause a significant reduction in treatment efficacy for patients with cancer (1). Request PDF | Iron-doxorubicin prodrug loaded liposome nanogenerator programs multimodal ferroptosis for efficient cancer therapy | Ferroptosis is a new mode of cell death, which can be induced by . Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to . 2021 Dec;161:116-129. However, the mechanism of DXZ in ferroptosis and cardiomyopathy remains unclear. The major characteristics of ferroptosis is the accumulation of lipid peroxidation. . Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Doxorubicin (DOX) is the most effective and extensively used treatment for many tumors. Doxorubicin (DOX) is an anticancer drug widely used in cancer treatments, including breast cancer (), prostate cancer (), and some other types of malignancies (3, 4).However, the clinical use of anthracyclines is limited due to their cardiotoxic effects, including irreversible degenerative cardiomyopathy and congestive heart ().DOX induces injuries of multiple organs, for example . Title:Protectors of the Mitochondrial Permeability Transition Pore Activated by Iron and Doxorubicin VOLUME: 21 ISSUE: 6 Author(s):Tatiana A. Fedotcheva and Nadezhda I. Fedotcheva* Affiliation:Science Research Laboratory of Pharmacology, Faculty of Medical Biology, N. I. Pirogov Russian National Medical Research University, Ministry of Health of the Russian Federation, Moscow, Institute of . Mice administered doxorubicin and ferrostatin-1, a ferroptosis inhibitor, have improved survival 52,53 . Ferroptosis, a form of cell death that is initiated by iron-dependent lipid peroxidation of the cell membrane, is associated with cellular antioxidant capacity and has been reported to be induced by doxorubicin, hence is a potential target for protection against doxorubicin-induced cardiotoxicity [24,27]. Objective: The study was conducted on isolated liver and heart mitochondria. Combination of chemotherapeutic drugs such as tmozolomide, cisplatin, doxorubicin with ferroptosis inducer erastin resulted in a remarkable synergistic effect on tumor treatment . Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity. Apoptosis, necrosis and ferroptosis of cardiomyocyte have been demonstrated to play an important role in DOX-induced cardiotoxicity [22,33,37]. , 11 ( 2020 ) , Article 756 , 10.1038/s41419-020-02948-2 CrossRef View Record in Scopus Google Scholar Nuggets Vs Clippers Head-to Head, California Newspapers Archives, A Company's Environmental Sustainability Strategy Concerns, Sunset Beach Campground Reservations, Vrbo Palm Springs House With Pool, Sheet Pan Parmesan Chicken And Potatoes, Seattle Pacific Gymnastics, Wild 'n Out Games You Can Play With Friends, Texas Black Widow Serial Killer,