ferrostatin-1 and Liver-Neoplasms

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

Hepatocellular carcinoma (HCC) is a common type of solid liver carcinoma. Regulating ferroptosis is important for the treatment of HCC. SSPH I is an anti-HCC steroidal saponin isolated from Schizocapsa plantaginea Hance. In this study, we found that SSPH I exerted significant anti-proliferation and anti-migration effects on HepG2 cell, ferroptosis inhibitor ferrostatin-1 or iron chelator ciclopirox partly attenuated the effect of SSPH I. SSPH I also induced apoptosis and G2/M phase cell cycle arrest. ROS accumulation, glutathione depletion and malondialdehyde accumulation were detected after SSPH I treatment, which leads to lipid peroxidation. Ferrostatin-1 or ciclopirox showed a significant antagonist effect towards SSPH I induced lipid peroxidation. Furthermore, typical morphologic changes of ferroptosis, such as increasing density of mitochondrial membrane and reduction of mitochondrial cristae were observed in HepG2 cells after SSPH I treatment. SSPH I does not regulate the xCT protein. Interestingly, SSPH I elevated the expression levels of SLC7A5, which is the negative regulator of ferroptosis. In contrast, SSPH I upregulated the expression of TFR and Fpn proteins, leading to the accumulation of Fe

Topics: Carcinoma, Hepatocellular; Ciclopirox; Ferroptosis; Hep G2 Cells; Humans; Iron; Liver Neoplasms; Reactive Oxygen Species; Saponins

The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC). In our report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Death; Cell Line, Tumor; Cell Survival; Cyclohexylamines; Deferoxamine; Extracellular Signal-Regulated MAP Kinases; Humans; Iron; Iron Regulatory Protein 2; Liver Neoplasms; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Niacinamide; Oxidative Stress; Phenylenediamines; Phenylurea Compounds; Protein Kinase Inhibitors; raf Kinases; RNA Interference; Siderophores; Sorafenib