Ferroptosis, a new form of cell death, and its relationships with tumourous diseases.
TL;DR: The induction mechanisms and regulatory pathways of ferroptosis, a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron‐dependent lipid peroxide accumulation, are summarized and their roles in human tumourous diseases are clarified.
Abstract: Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron-dependent lipid peroxide accumulation. Ferroptotic cell death is characterized by cytological changes, including cell volume shrinkage and increased mitochondrial membrane density. Ferroptosis can be induced by two classes of small-molecule substances known as class 1 (system Xc- inhibitors) and class 2 ferroptosis inducers [glutathione peroxidase 4 (GPx4) inhibitors]. In addition to these small-molecule substances, a number of drugs (e.g. sorafenib, artemisinin and its derivatives) can induce ferroptosis. Various factors, such as the mevalonate (MVA) and sulphur-transfer pathways, play pivotal roles in the regulation of ferroptosis. Ferroptosis plays an unneglectable role in regulating the growth and proliferation of some types of tumour cells, such as lymphocytoma, ductal cell cancer of the pancreas, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Here, we will first introduce the discovery of and research pertaining to ferroptosis; then summarize the induction mechanisms and regulatory pathways of ferroptosis; and finally, further elucidate the roles of ferroptosis in human tumourous diseases.
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TL;DR: The current findings of ferroptosis regulation are reviewed and especially focus on the function of ncRNAs in mediating the process of cell ferroPTotic death and on how ferroaptosis was in relation to other regulated cell deaths.
Abstract: Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.
705 citations
TL;DR: The history of observations consistent with the current definition of ferroptosis, as well as the advances that contributed to the emergence of the concept, are described.
539 citations
TL;DR: The current strategies of cancer therapy based on ferroptosis will be elaborated, the design considerations and the advantages and limitations are highlighted, and finally a future perspective on this emerging field is given.
Abstract: Ferroptosis, a new form of regulated cell death that is iron- and reactive oxygen species dependent, has attracted much attention in the research communities of biochemistry, oncology, and especially material sciences Since the first demonstration in 2012, a series of strategies have been developed to induce ferroptosis of cancer cells, including the use of nanomaterials, clinical drugs, experimental compounds, and genes A plethora of research work has outlined the blueprint of ferroptosis as a new option for cancer therapy However, the published ferroptosis-related reviews have mainly focused on the mechanisms and pathways of ferroptosis, which motivated this contribution to bridge the gap between biological significance and material design Therefore, it is timely to summarize the previous efforts on the emerging strategies for inducing ferroptosis and shed light on future directions for using such a tool to fight against cancer Here, the current strategies of cancer therapy based on ferroptosis will be elaborated, the design considerations and the advantages and limitations are highlighted, and finally a future perspective on this emerging field is given
461 citations
TL;DR: Evidence of the manifestation of ferroptosis in vivo in iron overload mice mutants is emerging and a concerted synchronization of iron availability, ROS generation, glutamate excess and cysteine deficit leads to ferroPTosis.
455 citations
TL;DR: This study demonstrates that ferroptosis is closely associated with intestinal I/R injury, and that ACSL4 has a critical role in this lethal process, and suggests a unique and effective mechanistic approach for intestinal I-R injury prevention and treatment.
Abstract: Ferroptosis is a recently identified form of regulated cell death defined by the iron-dependent accumulation of lipid reactive oxygen species. Ferroptosis has been studied in various diseases such as cancer, Parkinson’s disease, and stroke. However, the exact function and mechanism of ferroptosis in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. Considering the unique conditions required for ferroptosis, we hypothesize that ischemia promotes ferroptosis immediately after intestinal reperfusion. In contrast to conventional strategies employed in I/R studies, we focused on the ischemic phase. Here we verified ferroptosis by assessing proferroptotic changes after ischemia along with protein and lipid peroxidation levels during reperfusion. The inhibition of ferroptosis by liproxstatin-1 ameliorated I/R-induced intestinal injury. Acyl-CoA synthetase long-chain family member 4 (ACSL4), which is a key enzyme that regulates lipid composition, has been shown to contribute to the execution of ferroptosis, but its role in I/R needs clarification. In the present study, we used rosiglitazone (ROSI) and siRNA to inhibit ischemia/hypoxia-induced ACSL4 in vivo and in vitro. The results demonstrated that ACSL4 inhibition before reperfusion protected against ferroptosis and cell death. Further investigation revealed that special protein 1 (Sp1) was a crucial transcription factor that increased ACSL4 transcription by binding to the ACSL4 promoter region. Collectively, this study demonstrates that ferroptosis is closely associated with intestinal I/R injury, and that ACSL4 has a critical role in this lethal process. Sp1 is an important factor in promoting ACSL4 expression. These results suggest a unique and effective mechanistic approach for intestinal I/R injury prevention and treatment.
417 citations
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TL;DR: A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination, and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake.
Abstract: The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
52,293 citations
TL;DR: Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development, and participates in at least some types of therapeutically induced tumour regression.
Abstract: The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.
15,416 citations
"Ferroptosis, a new form of cell dea..." refers background in this paper
...defined a type of hepatatrophy-associated ‘automatically programmed’ cell death as ‘apoptosis’ [30], which is characterized by typical morphological changes such as chromosome shrinkage, chromatin condensation and peripheralization, and round or oval cytoplasmic fragment formation [1, 30]....
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TL;DR: This paper identified the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes.
7,192 citations
"Ferroptosis, a new form of cell dea..." refers background or methods in this paper
...used the term ‘ferroptosis’ to describe this type of cell death caused by the accumulation of iron-dependent lipid peroxides [1]....
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...Ferroptosis does not result in morphological changes similar to the chromatin condensation that occurs during apoptosis, the loss of plasma membrane integrity that occurs during necrosis, or the formation of double membrane-layered autophagic vacuoles that occurs during autophagy; instead, it manifests primarily as mitochondrial shrinkage and increased mitochondrial membrane density [1] (Table 1)....
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...This effect could be inhibited by b-mercaptoethanol (bME) [1], because b-ME can enhance cysteine uptake through other pathways [39]....
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...Ferroptosis differs from apoptosis and necrosis in the traditional sense and results from the accumulation of iron-dependent lipid peroxide [1]....
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...Ferroptosis differs considerably from other cell death types, such as apoptosis, necrosis, and autophagy, in various aspects, including morphology, biochemistry and genetics [1, 14]....
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TL;DR: It is demonstrated that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer and confers a modest survival advantage over treatment with5-FU.
Abstract: PURPOSEMost patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer.PATIENTS AND METHODSOne hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofs...
5,515 citations
"Ferroptosis, a new form of cell dea..." refers background in this paper
...Pancreatic carcinoma is a highly fatal tumour, and even standardized pharmacotherapy can only prolong patients’ survival duration by less than 6 months [90]....
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TL;DR: Targeted metabolomic profiling and chemoproteomics revealed that GPX4 is an essential regulator of ferroptotic cancer cell death and sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPx4-regulated ferroPTosis.
3,457 citations