Ferroptosis-driven nanotherapeutics for cancer treatment

Shan, Xinzhu; Li, Shumeng; Sun, Bingjun; Qin, Chen; Sun, Jin; Zhang, He; Luo, Cong

doi:10.1016/j.jconrel.2020.01.008

Cited by 161 publications

(115 citation statements)

References 86 publications

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“…However, there are still some unsolved problems about the molecular pathways of N-GQDs inducing mitochondrial oxidative stress and the specific targets of N-GQDs causing ferroptosis, which should be addressed and clarified before allowing them in biomedical applications. Even though the induction of ferroptosis by GQDs could be expected in cancer therapy via inhibiting cancer cell growth like other nanoparticles [ 53 ], it is still a probably serious consequence in response to GQDs in normal tissues, especially the brain that is vulnerable to LPO. The findings advance our understanding of cytotoxicity of GQDs in microglia and provide valuable information for risk assessment of this unique nanoparticles.…”

Section: Discussionmentioning

confidence: 99%

Induction of ferroptosis in response to graphene quantum dots through mitochondrial oxidative stress in microglia

Liu

et al. 2020

Part Fibre Toxicol

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Background Graphene quantum dots (GQDs) provide a bright prospect in the biomedical application because they contain low-toxic compounds and promise imaging of deep tissues and tiny vascular structures. However, the biosafety of this novel QDs has not been thoroughly evaluated, especially in the central nervous system (CNS). The microarray analysis provides a hint that nitrogen-doped GQDs (N-GQDs) exposure could cause ferroptosis in microglia, which is a novel form of cell death dependent on iron overload and lipid peroxidation. Results The cytosolic iron overload, glutathione (GSH) depletion, excessive reactive oxygen species (ROS) production and lipid peroxidation (LPO) were observed in microglial BV2 cells treated with N-GQDs, which indicated that N-GQDs could damage the iron metabolism and redox balance in microglia. The pre-treatments of a specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) and an iron chelater Deferoxamine mesylate (DFO) not only inhibited cell death, but also alleviated iron overload, LPO and alternations in ferroptosis biomarkers in microglia, which were caused by N-GQDs. When assessing the potential mechanisms of N-GQDs causing ferroptosis in microglia, we found that the iron content, ROS generation and LPO level in mitochondria of BV2 cells all enhanced after N-GQDs exposure. When the antioxidant ability of mitochondria was increased by the pre-treatment of a mitochondria targeted ROS scavenger MitoTEMPO, the ferroptotic biological changes were effectively reversed in BV2 cells treated with N-GQDs, which indicated that the N-GQDs-induced ferroptosis in microglia could be attributed to the mitochondrial oxidative stress. Additionally, amino functionalized GQDs (A-GQDs) elicited milder redox imbalance in mitochondria and resulted in less ferroptotic effects than N-GQDs in microglia, which suggested a slight protection of amino group functionalization in GQDs causing ferroptosis. Conclusion N-GQDs exposure caused ferroptosis in microglia via inducing mitochondrial oxidative stress, and the ferroptotic effects induced by A-GQDs were milder than N-GQDs when the exposure method is same. This study will not only provide new insights in the GQDs-induced cell damage performed in multiple types of cell death, but also in the influence of chemical modification on the toxicity of GQDs.

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Section: Discussionmentioning

confidence: 99%

Induction of ferroptosis in response to graphene quantum dots through mitochondrial oxidative stress in microglia

Liu

et al. 2020

Part Fibre Toxicol

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“…Although initial research showed that ferroptosis may be different from the classical cell death (e.g., apoptosis, necrosis, and autophagy-dependent cell death) (Dixon et al, 2012), recent studies demonstrate that there is a close relationship between ferroptosis, necrosis, and autophagy (Chen M.S. et al, 2017;Muller et al, 2017;Li et al, 2020;Lin et al, 2020;Liu et al, 2020c;Xie et al, 2020a). Ferroptotic cells usually exhibit cell membrane rupture and the release of intracellular contents, especially damage-associated molecular patterns (DAMPs) (Wen et al, 2019;Dai et al, 2020b), and are therefore classified as a type of regulated necrosis (Conrad et al, 2016).…”

Section: The Basic Properties Of Ferroptosismentioning

confidence: 99%

Oxidative Damage and Antioxidant Defense in Ferroptosis

Kuang

Liu

Tang

et al. 2020

Front. Cell Dev. Biol.

354

197

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Many new types of regulated cell death have been recently implicated in human health and disease. These regulated cell deaths have different morphological, genetic, biochemical, and functional hallmarks. Ferroptosis was originally described as a carcinogenic RAS-dependent non-apoptotic cell death, and is now defined as a type of regulated necrosis characterized by iron accumulation, lipid peroxidation, and the release of damage-associated molecular patterns (DAMPs). Multiple oxidative and antioxidant systems, acting together autophagy machinery, shape the process of lipid peroxidation during ferroptosis. In particular, the production of reactive oxygen species (ROS) that depends on the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and the mitochondrial respiratory chain promotes lipid peroxidation by lipoxygenase (ALOX) or cytochrome P450 reductase (POR). In contrast, the glutathione (GSH), coenzyme Q10 (CoQ10), and tetrahydrobiopterin (BH 4) system limits oxidative damage during ferroptosis. These antioxidant processes are further transcriptionally regulated by nuclear factor, erythroid 2-like 2 (NFE2L2/NRF2), whereas membrane repair during ferroptotic damage requires the activation of endosomal sorting complexes required for transport (ESCRT)-III. A further understanding of the process and function of ferroptosis may provide precise treatment strategies for disease.

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“…Although researches on ferroptosis in cancer therapy have progressed rapidly in recent years, great problems for its clinical application remain, such as the low solubility and poor membrane permeability of ferroptosis-inducing anticancer drugs or the off-target toxicity to normal cells and tissues ( 119 – 121 ). In view of this plight, development of ferroptosis-driven nanotherapeutics seems to be a promising stratage ( 122 ). Ferroptosis-driven nanotherapeutics work in three main ways: First, they can trigger or promote Fenton reactions in tumor cells ( 123 ).…”

Section: Ferroptosis-driven Nanotherapeutics and Other Novel Waysmentioning

confidence: 99%

Ferroptosis in Cancer Treatment: Another Way to Rome

Luo

et al. 2020

Front. Oncol.

124

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Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis and the development of diseases, especially cancers. Inducing ferroptosis leads to mitochondrial dysfunction and toxic lipid peroxidation in cells, which plays a pivotal role in suppressing cancer growth and progression. Here, we reviewed the existing studies about the molecular mechanisms of ferroptosis involved in different antitumor treatments, such as chemotherapy, targeted therapy, radiotherapy, and immunotherapy. We focused in particular on the distinct combinatorial therapeutic effects such as the synergistic sensitization effect and the drug-resistance reversal achieved when using ferroptosis inducers with conventional cancer therapy. Finally, we discussed the challenges and opportunities in clinical applications of ferroptosis. The application of nanotechnolgy and other novel technologies may provide a new direction in ferroptosis-driven cancer therapies.

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Ferroptosis-driven nanotherapeutics for cancer treatment

Cited by 161 publications

References 86 publications

Induction of ferroptosis in response to graphene quantum dots through mitochondrial oxidative stress in microglia

Induction of ferroptosis in response to graphene quantum dots through mitochondrial oxidative stress in microglia

Oxidative Damage and Antioxidant Defense in Ferroptosis

Ferroptosis in Cancer Treatment: Another Way to Rome

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