ferrostatin-1 and liproxstatin-1

Cerebrovascular diseases, such as ischemic stroke, pose serious medical challenges worldwide due to their high morbidity and mortality and limitations in clinical treatment strategies. Studies have shown that reactive oxygen species (ROS)-mediated inflammation, excitotoxicity, and programmed cell death of each neurovascular unit during post-stroke hypoxia and reperfusion play an important role in the pathological cascade. Ferroptosis, a programmed cell death characterized by iron-regulated accumulation of lipid peroxidation, is caused by abnormal metabolism of lipids, glutathione (GSH), and iron, and can accelerate acute central nervous system injury. Recent studies have gradually uncovered the pathological process of ferroptosis in the neurovascular unit of acute stroke. Some drugs such as iron chelators, ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) can protect nerves after neurovascular unit injury in acute stroke by inhibiting ferroptosis. In addition, combined with our previous studies on ferroptosis mediated by natural compounds in ischemic stroke, this review summarized the progress in the regulation mechanism of natural chemical components and herbal chemical components on ferroptosis in recent years, in order to provide reference information for future research on ferroptosis and lead compounds for the development of ferroptosis inhibitors.

Topics: Cyclohexylamines; Ferroptosis; Glutathione; Humans; Iron; Ischemic Stroke; Lipid Peroxidation; Oxidative Stress; Phenylenediamines; Quinoxalines; Reactive Oxygen Species; Spiro Compounds

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia-reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.

Topics: alpha-Tocopherol; Animals; Autophagy; Chemical and Drug Induced Liver Injury; Cyclohexylamines; Cysteine; Ferroptosis; Glutathione; Heme; Humans; Iron; Kelch-Like ECH-Associated Protein 1; Lipid Peroxidation; Lipoxygenase; Liver Diseases; Liver Neoplasms; Oxidative Stress; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Quinoxalines; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Sorafenib; Spiro Compounds; Sulfasalazine; Tumor Suppressor Protein p53

Ferroptosis is a widely recognized process of regulated cell death linking redox state, metabolism, and human health. It is considered a defense mechanism against extensive lipid peroxidation, a complex process that may disrupt the membrane integrity, eventually leading to toxic cellular injury. Ferroptosis is controlled by iron, reactive oxygen species, and polyunsaturated fatty acids. Accumulating evidence has addressed that ferroptosis plays an unneglectable role in regulating the development and progression of multiple pathologies of the liver, including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatosis, hepatic ischemia-reperfusion injury, and liver failure. This review may increase our understating of the cellular and molecular mechanisms of liver disease progression and establish the foundation of strategies for pharmacological intervention.

Topics: Animals; Antineoplastic Agents; Caffeic Acids; Carcinoma, Hepatocellular; Cycloheximide; Cyclohexylamines; Deferoxamine; Disease Models, Animal; Disease Progression; Fatty Acids, Unsaturated; Ferroptosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Lipid Peroxidation; Liver; Liver Cirrhosis; Liver Failure; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Phenylenediamines; Quinoxalines; Reactive Oxygen Species; Reperfusion Injury; Spiro Compounds

Ferroptosis is a recently described form of regulated necrotic cell death, which appears to contribute to a number of diseases, such as tissue ischemia/reperfusion injury, acute renal failure, and neurodegeneration. A hallmark of ferroptosis is iron-dependent lipid peroxidation, which can be inhibited by the key ferroptosis regulator glutathione peroxidase 4(Gpx4), radical trapping antioxidants and ferroptosis-specific inhibitors, such as ferrostatins and liproxstatins, as well as iron chelation. Although great strides have been made towards a better understanding of the proximate signals of distinctive lipid peroxides in ferroptosis, still little is known about the mechanistic implication of iron in the ferroptotic process. Hence, this review aims at summarizing recent advances in our understanding to what is known about enzymatic and nonenzymatic routes of lipid peroxidation, the involvement of iron in this process and the identification of novel players in ferroptotic cell death. Additionally, we review early works carried out long time before the term "ferroptosis" was actually introduced but which were instrumental in a better understanding of the role of ferroptosis in physiological and pathophysiological contexts. © 2017 IUBMB Life, 69(6):423-434, 2017.

Topics: Animals; Antioxidants; Cell Death; Cyclohexylamines; Glutathione Peroxidase; Humans; Iron; Iron Chelating Agents; Iron Metabolism Disorders; Lipid Peroxidation; Necrosis; Neuroaxonal Dystrophies; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Quinoxalines; Renal Insufficiency; Reperfusion Injury; Spiro Compounds

Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever be able to prevent due to the unregulated nature of this form of cell death. However, given our growing understanding of the existence of regulated forms of necrosis and the roles of key enzymes of these pathways, e.g., kinases, peroxidases, etc., the possibility emerges to identify efficient and selective small molecule inhibitors of pathologic necrosis. Here, we review the published literature on small molecule inhibition of regulated necrosis and provide an outlook on how combination therapy may be most effective in treatment of necrosis-associated clinical situations like stroke, myocardial infarction, sepsis, cancer and solid organ transplantation.

Topics: Animals; Apoptosis; Cyclohexylamines; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Mice; Necrosis; Organic Chemicals; Phenylenediamines; Protein Kinases; Pyridazines; Quinoxalines; Receptor-Interacting Protein Serine-Threonine Kinases; Spiro Compounds; Sulfones

Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4). This lethal process is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids. Cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression may be sensitized to this process. Conversely, a number of small molecule inhibitors of ferroptosis have been identified, including ferrostatin-1 and liproxstatin-1, which can block pathological cell death events in brain, kidney and other tissues. Recent work has identified a number of genes required for ferroptosis, including those involved in lipid and amino acid metabolism. Outstanding questions include the relationship between ferroptosis and other forms of cell death, and whether activation or inhibition of ferroptosis can be exploited to achieve desirable therapeutic ends.

Topics: Cell Death; Cell Membrane; Cyclohexylamines; Fatty Acids, Unsaturated; Glutathione; Glutathione Peroxidase; Iron; Neoplasms; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Quinoxalines; Reactive Oxygen Species; Spiro Compounds

Triple-negative breast cancer (TNBC), lacking targeted therapies currently, is susceptible to ferroptosis, a recently defined form of cell death.. To evaluate the anticancer activity of Shuganning injection (SGNI), a traditional Chinese patent medicine, on TNBC cells; To elucidate the mechanism of SGNI induced ferroptosis.. The anticancer activity of SGNI was examined via in vitro cell proliferation assays and in vivo xenograft growth assay. Ferroptosis was determined by flow-cytometric analysis of lipid ROS, labile iron pool measurement, and propidium iodide exclusion assay. The dependency on heme oxygenase 1 (HO-1) of SGNI induced ferroptosis was confirmed by genetic knockdown and pharmacological inhibition of the protein.. SGNI selectively inhibited the proliferation of TNBC cells compared to non-TNBC breast cancer cells and normal cells. The cell death induced by SGNI in TNBC cells showed distinct morphology from apoptosis and could not be rescued by the pan-caspase inhibitor Z-VAD(OMe)-FMK. On the other hand, SGNI induced cell death was blocked by the lipid ROS scavengers ferrostatin-1 and liproxstatin-1, the acyl-CoA synthetase long chain family member 4 inhibitor rosiglitazone, and the iron chelators 1,10-phenanthroline and deferoxamine. These data indicated that SGNI induced a ferroptotic cell death of TNBC cells. Mechanistically, SGNI induced ferroptosis was dependent on HO-1, which promotes intracellular labile iron pool accumulation, and was alleviated by HO-1 knockdown and inhibition by tin protoporphyrin IX. In line with the in vitro data, SGNI significantly inhibited the xenograft growth of TNBC cell line MD-MB-231 in nude mice.. Collectively, our study elaborates on a promising regimen for TNBC treatment through induction of ferroptosis by SGNI, a traditional Chinese patent medicine currently available in the clinic, which merits further investigation.

Topics: Animals; Cell Death; Cell Line, Tumor; Cell Proliferation; China; Cyclohexylamines; Drugs, Chinese Herbal; Female; Ferroptosis; Heme Oxygenase-1; Humans; Iron; Lipid Peroxidation; Medicine, Chinese Traditional; Mice; Mice, Nude; Phenylenediamines; Quinoxalines; Spiro Compounds; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Even though long non-coding RNA (lncRNA) MEG8 plays vital roles in carcinogenesis of malignances, its roles and mechanisms in hemangioma remain unknown. Therefore, we evaluate the oncogenic roles of MEG8 in hemangioma. Small interfering RNA (siRNA)-mediated depletion of MEG8 inhibited the proliferation and increased MDA level in human hemangioma endothelial cells (HemECs). The inhibitors of ferroptosis (ferrostatin-1 and liproxstatin-1) abolished the MEG8 silence induced cell viability loss. Knockdown of MEG8 increased the miR-497-5p expression and reduced the mRNA and protein levels of NOTCH2. Using a dual-luciferase assay, we confirmed the binding between MEG8 and miR-497-5p, and between the miR-497-5p and 3'UTR of NOTCH2. We further found that silencing MEG8 significantly decreased the expressions of SLC7A11 and GPX4 both in mRNA and protein level and had no effect on the level of AIFM2. Importantly, blocking miR-497-5p abrogated the effects of MEG8 loss on cell viability, MDA level and expression levels of NOTCH2, SLC7A11 and GPX4 in HemECs. Taken together, our results suggested that knockdown of long non-coding RNA MEG8 inhibited the proliferation and induced the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Topics: Amino Acid Transport System y+; Apoptosis Regulatory Proteins; Base Sequence; Cell Proliferation; Cyclohexylamines; Down-Regulation; Endothelial Cells; Ferroptosis; Gene Silencing; Hemangioma; Humans; MicroRNAs; Mitochondrial Proteins; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Quinoxalines; Receptor, Notch2; RNA, Long Noncoding; RNA, Small Interfering; Spiro Compounds

Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors [ferrostatin-1 (Fer-1) and Liproxstatin-1] and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (

Topics: Animals; Cell Death; Cell Line; Cyclohexylamines; Deferoxamine; Endothelial Cells; Ferroptosis; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidases; Phenylenediamines; Quinoxalines; Rats; Rats, Sprague-Dawley; Siderophores; Smoke; Spiro Compounds; Tissue Inhibitor of Metalloproteinase-1

Pancreatic cancer is one of the most lethal types of cancer with a mortality rate of almost 95%. Treatment with current chemotherapeutic drugs has limited success due to poor responses. Therefore, the development of novel drugs or effective combination therapies is urgently required. Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels. In the present study, we demonstrated that PL induced cancer cell death through, at least in part, the induction of ferroptosis, as the cancer cell-killing activity was inhibited by the antioxidant, N‑acetylcysteine, ferroptosis inhibitors (ferrostatin‑1 and liproxstatin‑1) and the iron chelator, deferoxamine (DFO), but not by the apoptosis inhibitor, Z-VAD-FMK, or the necrosis inhibitor, necrostatin‑1. Cotylenin A (CN‑A; a plant growth regulator) exhibits potent antitumor activities in several cancer cell lines, including pancreatic cancer cell lines. We found that CN‑A and PL synergistically induced the death of pancreatic cancer MIAPaCa‑2 and PANC‑1 cells for 16 h. CN‑A enhanced the induction of ROS by PL for 4 h. The synergistic induction of cell death was also abrogated by the ferroptosis inhibitors and DFO. The present results revealed that clinically approved sulfasalazine (SSZ), a ferroptosis inducer, enhanced the death of pancreatic cancer cells induced by PL and the combined effects were abrogated by the ferroptosis inhibitors and DFO. SSZ further enhanced the cancer cell-killing activities induced by combined treatment with PL plus CN‑A. On the other hand, the synergistic induction of cell death by PL and CN‑A was not observed in mouse embryonic fibroblasts (MEFs), and SSZ did not enhance the death of MEFs induced by PL plus CN‑A. These results suggest that the triple combined treatment with PL, CN‑A and SSZ is highly effective against pancreatic cancer.

Topics: Acetylcysteine; Amino Acid Chloromethyl Ketones; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Cell Line, Tumor; Cyclohexylamines; Deferoxamine; Dioxolanes; Diterpenes; Drug Synergism; Fibroblasts; Humans; Iron; Mice; Pancreatic Neoplasms; Phenylenediamines; Quinoxalines; Reactive Oxygen Species; Spiro Compounds; Sulfasalazine