Small-Molecule Inhibitors of Reactive Oxygen Species Production

Sassetti, Elisa; Clausen, Mads Hartvig; Laraia, Luca

doi:10.1021/acs.jmedchem.0c01914

Cited by 45 publications

(22 citation statements)

References 217 publications

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“…Similar to a previous report ( Li et al, 2021 ), we found that lycorine treatment stimulated high levels of ROS production in HSFs and produced high levels of ROS appeared to be responsible for the pro-apoptotic and anti-fibrotic activities of lycorine. Supportively, treatment with NAC, a ROS scavenger ( Sassetti et al, 2021 ), alone did not affect the apoptosis of HSFs, but significantly mitigated or abrogated the pro-apoptotic and anti-fibrotic effects of lycorine in HSFs by increasing the MMP, reducing cytoplasm cyt-C translocation and apoptosis.…”

Section: Discussionmentioning

confidence: 93%

Lycorine Inhibits Hypertrophic Scar Formation by Inducing ROS-Mediated Apoptosis

Dong

Zhao

et al. 2022

Front. Bioeng. Biotechnol.

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Background: Hypertrophic scar (HS) is a fibrotic cutaneous disease with few effective therapies. Lycorine is a drug with pro-apoptotic ability and anti-fibrosis potential. This study aimed to test whether lycorine could trigger the apoptosis of hypertrophic scar fibroblasts (HSFs) to inhibit HS formation.Methods: The proapoptotic and anti-fibrosis effects of lycorine on the viability and apoptosis of human primary HSFs and their reactive oxygen species (ROS) production as well as a rabbit ear model of HS were determined by CCK-8, flow cytometry, Western blot, immunofluorescence, transwell migration, collagen gel contraction assays.Results: Lycorine treatment selectively decreased the viability of HSFs, and induced their apoptosis, but not normal fibroblasts (NFs). Lycorine treatment increased the relative levels of Bax and cleaved PARP expression, cytochrome C cytoplasm translocation, but decreased Bcl-2, caspase-3 and caspase-9 expression, the mitochondrial membrane potential (MMP) in HSFs. Lycorine inhibited the migration and contraction of HSFs, and reduced the expression of collagen I, collagen III and α-SMA. Mechanistically, lycorine treatment stimulated high levels of ROS production, leading to apoptosis of HSFs while treatment with NAC, a ROS inhibitor, significantly mitigated or abrogated the pro-apoptotic and antifibrotic activity of lycorine in HSFs. Moreover, lycorine treatment mitigated the severity of HS in rabbit ears by inducing fibroblast apoptosis.Conclusion: These results indicate that lycorine has a potent anti-fibrotic activity and is a potential drug for intervention of HS.

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Section: Discussionmentioning

confidence: 93%

Lycorine Inhibits Hypertrophic Scar Formation by Inducing ROS-Mediated Apoptosis

Dong

Zhao

et al. 2022

Front. Bioeng. Biotechnol.

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“…The same trend was observed for positive control which further confirms the potency of the purine derivatives towards the removal of excess iron from cells via its chelation. It is known that the generation of ROS is directly dependent on the iron concentration and Fe 2+ induces such intracellular processes [15b,28] . We checked the effect of added purine derivatives on ROS concentration inside the cells by measuring the DCF fluorescence intensity [29] .…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Erastin‐Induced Ferroptotic Cell Death by Purine‐Based Chelators

et al. 2022

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Ferroptosis is a cell death event caused by increased lipid peroxidation leading to iron‐dependent oxidative stress and is associated with a wide variety of diseases. In recent years, ferroptosis inhibition has emerged as a novel strategy to target different pathologies. Here, we report the synthesis of two purine derivatives, 1 and 2, for iron chelation strategy and evaluate their potency to inhibit erastin‐induced ferroptosis. Both compounds showed efficient iron chelation in solution as well as in cellular environment. The crystal structure of the purine derivatives with iron demonstrated a 2 : 1 (ligand to metal center) stoichiometry for iron and purine derivative complexation. The synthesized compounds also decrease the reactive oxygen species concentration in cell cultures. Compound 2 showed better potency towards the prevention of ferroptotic cell death as compared to commercially available iron chelator in the erastin‐induced ferroptosis cell culture model. Such purine analogues are potential functional scaffolds for the development of target molecules for ferroptosis inhibition.

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“…Requirement 2: ROS and radicals. As reviewed recently by Sassetti et al [ 20 ], the main source of intracellular ROS are mitochondria, i.e., incomplete reduction within the mitochondrial respiratory chain (superoxide). Furthermore, enzymes in the endoplasmatic reticulum, peroxisomes and the plasma membrane (such as NOX, NADPH oxidases) as well as non-enzymatically via the Fenton reaction represent sources of ROS [ 9 , 20 ] that might represent the starting point of ferroptosis induction—provided that the other mentioned requirements are fulfilled.…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

Bekric

Ocker

Mayr

et al. 2022

Cancers

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Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.

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Small-Molecule Inhibitors of Reactive Oxygen Species Production

Cited by 45 publications

References 217 publications

Lycorine Inhibits Hypertrophic Scar Formation by Inducing ROS-Mediated Apoptosis

Lycorine Inhibits Hypertrophic Scar Formation by Inducing ROS-Mediated Apoptosis

Inhibiting Erastin‐Induced Ferroptotic Cell Death by Purine‐Based Chelators

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

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