Pharmacological Targeting of Ferroptosis in Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Mehdi Rabiee Valashedi ◽  
Amirsadegh Nikoo ◽  
Nima Najafi-Ghalehlou ◽  
Kazuo Tomita ◽  
Yoshikazu Kuwahara ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Antioxidant Defense ◽  
Lipid Peroxides ◽  
Antioxidant Defense System ◽  
The Past ◽  
Regulated Cell Death ◽  
Underlying Mechanisms ◽  
Excessive Accumulation ◽  
Tumor Cell Resistance

: Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.

Abstract P419: A Systematic Characterization of Brain Endothelial Cell Death in Intracerebral Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Maulana Ikhsan ◽  
Marietta Zille
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Brain Tissue ◽  
Vascular Integrity ◽  
Regulated Cell Death ◽  
Injury Mechanisms ◽  
Endothelial Cell Death ◽  
Cell Death Mechanisms ◽  
Underlying Mechanisms

Introduction: Intracerebral hemorrhage (ICH) is a type of stroke caused by the loss of vascular integrity leading to bleeding within the brain tissue. Hematoma-derived factors cause secondary injury mechanisms such as cell death days to weeks after the event and in regions distant from the primary insult. Increasing evidence suggests that hemoglobin released by the hematoma is one of the major contributors to neuronal injury in ICH. To date, it is unclear whether brain endothelial cells (EC) are similarly vulnerable to hemolysis products and undergo regulated cell death. Hypothesis: We hypothesized that brain EC undergo multiple, different modes of cell death after ICH and that the underlying mechanisms are different compared to neurons. Methods: We systematically investigated cell death mechanisms in brain EC after exposure to the hemolysis product hemin. We used chemical inhibitors of apoptosis, autophagy, ferroptosis, necroptosis, and parthanatos and assessed biochemical markers of these cell death modes. Results: Brain EC viability was concentration-dependently decreased, starting at higher hemin concentrations than neurons. Treatment of EC with ferroptosis inhibitors protective against hemin toxicity in neurons and against ICH in vivo showed that only N-acetylcysteine and deferoxamine protected brain EC, while ferrostatin-1 and U0126 did not abrogate EC death. The autophagy inhibitor bafilomycin A1 also reduced EC death and hemin increased the expression of the autophagy marker LC3. While inhibitors against apoptosis and parthanatos were not effective, the necroptosis inhibitor GSK872 demonstrated a partial protective effect. Conclusions: Our data suggest that ICH induces different mechanisms of death in EC (ferroptosis and autophagy) compared to neurons (ferroptosis and necroptosis) and may thus warrant a combinatorial therapeutic approach. Further investigations in human and ovine ICH brain tissue are ongoing.

scholarly journals Ferroptosis-mediated Crosstalk in the Tumor Microenvironment Implicated in Cancer Progression and Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yini Liu ◽  
Chunyan Duan ◽  
Rongyang Dai ◽  
Yi Zeng
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Lipid Peroxides ◽  
Antioxidant Systems ◽  
Biological Processes ◽  
The Novel ◽  
Regulated Cell Death ◽  
Novel Therapeutic Strategies

Ferroptosis is a recently recognized form of non-apoptotic regulated cell death and usually driven by iron-dependent lipid peroxidation and has arisen to play a significant role in cancer biology. Distinct from other types of cell death in morphology, genetics, and biochemistry, ferroptosis is characterized by the accumulation of lipid peroxides and lethal reactive oxygen species controlled by integrated oxidant and antioxidant systems. Increasing evidence indicates that a variety of biological processes, including amino acid, iron, lactate, and lipid metabolism, as well as glutathione, phospholipids, NADPH, and coenzyme Q10 biosynthesis, are closely related to ferroptosis sensitivity. Abnormal ferroptotic response may modulate cancer progression by reprogramming the tumor microenvironment (TME). The TME is widely associated with tumor occurrence because it is the carrier of tumor cells, which interacts with surrounding cells through the circulatory and the lymphatic system, thus influencing the development and progression of cancer. Furthermore, the metabolism processes play roles in maintaining the homeostasis and evolution of the TME. Here, this review focuses on the ferroptosis-mediated crosstalk in the TME, as well as discussing the novel therapeutic strategies for cancer treatment.

scholarly journals The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4576
Author(s):  
Hung-Yu Lin ◽  
Hui-Wen Ho ◽  
Yen-Hsiang Chang ◽  
Chun-Jui Wei ◽  
Pei-Yi Chu
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Drug Resistant ◽  
Therapeutic Targeting ◽  
The Past ◽  
Regulated Cell Death ◽  
Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

scholarly journals Molecular Mechanisms of Ferroptosis and Its Role in Pulmonary Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Ningning Tao ◽  
Kang Li ◽  
Jingjing Liu
Keyword(s):  
Cell Death ◽  
Effective Treatment ◽  
Pulmonary Disease ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Lipid Peroxides ◽  
Specific Mechanism ◽  
Disease Understanding ◽  
Biochemical Features ◽  
Excessive Accumulation

Ferroptosis is a new mode of cell death that is characterized by the excessive accumulation of iron and lipid peroxides. It has unique morphological changes and disparate biochemical features and plays an intricate role in many pathophysiological processes. A great deal of researches confirms that ferroptosis can be regulated by numerous molecules through different mechanisms, supporting great potentials for novel pharmacological therapeutics. Recently, several studies reveal that ferroptosis is also closely associated with the initiation and development of respiratory disease. Understanding the specific mechanism, the molecular trait of ferroptosis and their relationship with pulmonary disease could provide significant references regarding effective treatment of these obstinate disease.

scholarly journals Mitochondrial regulation of ferroptosis

2021 ◽  
Vol 220 (9) ◽  
Author(s):  
Boyi Gan
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Lipid Peroxides ◽  
Disease Treatment ◽  
Mitochondrial Regulation ◽  
Defense Systems ◽  
Regulated Cell Death ◽  
Mitochondrial Lipid ◽  
Mitochondria Functions ◽  
New Evidence

Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and cell death regulation. However, their role in ferroptosis has been unclear and somewhat controversial. In this Perspective, I summarize the diverse metabolic processes in mitochondria that actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems that detoxify mitochondrial lipid peroxides and protect against ferroptosis, present new evidence for the roles of mitochondria in regulating ferroptosis, and outline outstanding questions on this fascinating topic for future investigations. An in-depth understanding of mitochondria functions in ferroptosis will have important implications for both fundamental cell biology and disease treatment.

scholarly journals Ferroptosis and Its Multifaceted Roles in Cerebral Stroke

2021 ◽  
Vol 15 ◽  
Author(s):  
Yongfa Zhang ◽  
Xiaoyang Lu ◽  
Bai Tai ◽  
Weijia Li ◽  
Tao Li
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Iron Overload ◽  
Hemorrhagic Stroke ◽  
Lipid Peroxides ◽  
Cerebral Stroke ◽  
Intracellular Iron ◽  
Biological Features ◽  
Pathophysiological Process ◽  
Regulated Cell Death

Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system xc–, all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.

scholarly journals Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1975 ◽  
Author(s):  
Jasmine Wyatt ◽  
Manuel M. Müller ◽  
Mahvash Tavassoli
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Viral Proteins ◽  
Chemotherapeutic Agents ◽  
Tumour Cells ◽  
Specific Cell ◽  
Cancer Therapies ◽  
The Past

Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics.

PM10 impairs the antioxidant defense system and exacerbates oxidative stress driven cell death

2010 ◽  
Vol 193 (3) ◽  
pp. 209-216 ◽  
Author(s):  
Yolanda I. Chirino ◽  
Yesennia Sánchez-Pérez ◽  
Álvaro R. Osornio-Vargas ◽  
Rocío Morales-Bárcenas ◽  
María Concepción Gutiérrez-Ruíz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Antioxidant Defense ◽  
Antioxidant Defense System ◽  
Defense System

scholarly journals Biology of Ageing and Role of Dietary Antioxidants

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Cheng Peng ◽  
Xiaobo Wang ◽  
Jingnan Chen ◽  
Rui Jiao ◽  
Lijun Wang ◽  
...  
Keyword(s):  
Antioxidant Defense ◽  
Antioxidant Defense System ◽  
Fruit Flies ◽  
Dietary Antioxidants ◽  
Final Electron ◽  
Underlying Mechanisms ◽  
The One ◽  
Final Electron Acceptor ◽  
In Cells

Interest in relationship between diet and ageing is growing. Research has shown that dietary calorie restriction and some antioxidants extend lifespan in various ageing models. On the one hand, oxygen is essential to aerobic organisms because it is a final electron acceptor in mitochondria. On the other hand, oxygen is harmful because it can continuously generate reactive oxygen species (ROS), which are believed to be the factors causing ageing of an organism. To remove these ROS in cells, aerobic organisms possess an antioxidant defense system which consists of a series of enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). In addition, dietary antioxidants including ascorbic acid, vitamin A, vitamin C,α-tocopherol, and plant flavonoids are also able to scavenge ROS in cells and therefore theoretically can extend the lifespan of organisms. In this connection, various antioxidants including tea catechins, theaflavins, apple polyphenols, black rice anthocyanins, and blueberry polyphenols have been shown to be capable of extending the lifespan of fruit flies. The purpose of this review is to brief the literature on modern biological theories of ageing and role of dietary antioxidants in ageing as well as underlying mechanisms by which antioxidants can prolong the lifespan with focus on fruit flies as an model.

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