Nitroxides as Antioxidants and Anticancer Drugs

Lewandowski, Marcin; Gwoździński, Krzysztof

doi:10.3390/ijms18112490

Cited by 102 publications

(73 citation statements)

References 134 publications

(168 reference statements)

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“…The determination of dynamic radical changes in cellular microenvironment with non-invasive approaches is an essential mean for assessing the effectiveness of anticancer agents on cancer treatment [45][46][47][48]. As mentioned above, 5-FU's chemotherapeutic properties are attributed to thymidylate synthase (TS) activity inhibition, to mitochondrial ROS generation and the caspases cascade activation [49].…”

Section: Discussionmentioning

confidence: 99%

Detection of Superoxide Alterations Induced by 5-Fluorouracil on HeLa Cells with a Cell-Based Biosensor

et al. 2019

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Background: In vitro cell culture monitoring can be used as an indicator of cellular oxidative stress for the assessment of different chemotherapy agents. Methods: A cell-based bioelectric biosensor was used to detect alterations in superoxide levels in the culture medium of HeLa cervical cancer cells after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). The cytotoxic effects of 5-fluorouracil on HeLa cells were assessed by the MTT proliferation assay, whereas oxidative damage and induction of apoptosis were measured fluorometrically by the mitochondria-targeted MitoSOX™ Red and caspase-3 activation assays, respectively. Results: The results of this study indicate that 5-FU differentially affects superoxide production and caspase-3 activation when applied in cytotoxic concentrations against HeLa cells, while superoxide accumulation is in accordance with mitochondrial superoxide levels. Our findings suggest that changes in superoxide concentration could be detected with the biosensor in a non-invasive and rapid manner, thus allowing a reliable estimation of oxidative damage due to cell apoptosis. Conclusions: These findings may be useful for facilitating future high throughput screening of different chemotherapeutic drugs with a cytotoxic principle based on free radical production.

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Section: Discussionmentioning

confidence: 99%

Detection of Superoxide Alterations Induced by 5-Fluorouracil on HeLa Cells with a Cell-Based Biosensor

et al. 2019

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“…Nitroxides, such as TEMPO ((2,2,6,6tetramethylpiperidin-1-yl)oxyl), are stable radicals that have demonstrated to be useful both for biolm dispersion and for modulating inammation. [15][16][17][18][19][20][21][22][23] However, their incorporation into coatings and polymers has proven to be a tedious multistep endeavour which in turn limits their usefulness, albeit being a currently highly investigated material class. 23,24 In contrast, plasma polymerization is a one-step, rapid and solvent-free process that can be rapidly scaled to industrialscale.…”

Section: Introductionmentioning

confidence: 99%

It takes two for chronic wounds to heal: dispersing bacterial biofilm and modulating inflammation with dual action plasma coatings

et al. 2020

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Chronic wounds are affecting increasingly larger portions of the general population and their treatment has essentially remained unchanged for the past century. This lack of progress is due to the complex problem that chronic wounds are simultaneously infected and inflamed. Both aspects need to be addressed together to achieve a better healing outcome. Hence, we hereby demonstrate that the stable nitroxide radical (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) can be plasma polymerized into smooth coatings (TEMPOpp), as seen via atomic force microscopy, X-ray photoelectron spectroscopy and ellipsometry.Upon contact with water, these coatings leach nitroxides into aqueous supernatant, as measured via EPR. We then exploited the known cell-signalling qualities of TEMPO to change the cellular behaviour of bacteria and human cells that come into contact with the surfaces. Specifically, the TEMPOpp coatings not only suppressed biofilm formation of the opportunistic bacterium Staphylococcus epidermidis but also dispersed already formed biofilm in a dose-dependent manner; a crucial aspect in treating chronic wounds that contain bacterial biofilm. Thus the coatings' microbiological efficacy correlated with their thickness and the thickest coating was the most efficient. Furthermore, this dose-dependent effect was mirrored in significant cytokine reduction of activated THP-1 macrophages for the four cytokines TNF-a, IL-1b, IL-6 and IP-10. At the same time, the THP-1 cells retained their ability to adhere and colonize the surfaces, as verified via SEM imaging. Thus, summarily, we have exploited the unique qualities of plasma polymerized TEMPO coatings in targeting both infection and inflammation simultaneously; demonstrating a novel alternative to how chronic wounds could be treated in the future.

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“…These cell permeable small molecules show low toxicity and are currently being used in vivo as therapeutics for radiation induced macular degeneration and alopecia [ 25 ]. They act via various mechanisms such as superoxide dismutase (SOD) mimetics, free radical scavengers, and reversible MPO inhibitors with catalytic self-regeneration [ 26 , 27 ]. Importantly, nitroxides inhibit HOCl production by acting as substrates for MPO compound I [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Nitroxides Mitigate Neutrophil-Mediated Damage to the Myocardium after Experimental Myocardial Infarction in Rats

Kazzi

Shi

Vuong

et al. 2020

IJMS

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Reperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, thereby enhancing ventricular remodelling. Nitroxides inhibit MPO-mediated HOCl production, potentially ameliorating neutrophil-mediated damage. Aim: Assess the cardioprotective ability of nitroxide 4-methoxyTEMPO (4MetT) within the setting of AMI. Methods: Male Wistar rats were separated into 3 groups: SHAM, AMI/R, and AMI/R + 4MetT (15 mg/kg at surgery via oral gavage) and subjected to left descending coronary artery ligation for 30 min to generate an AMI, followed by reperfusion. One cohort of rats were sacrificed at 24 h post-reperfusion and another 28 days post-surgery (with 4MetT (15 mg/kg) administration twice daily). Results: 3-chlorotyrosine, a HOCl-specific damage marker, decreased within the heart of animals in the AMI/R + 4-MetT group 24 h post-AMI, indicating the drug inhibited MPO activity; however, there was no evident difference in either infarct size or myocardial scar size between the groups. Concurrently, MPO, NfκB, TNFα, and the oxidation marker malondialdehyde increased within the hearts, with 4-MetT only demonstrating a trend in decreasing MPO and TNF levels. Notably, 4MetT provided a significant improvement in cardiac function 28 days post-AMI, as assessed by echocardiography, indicating potential for 4-MetT as a treatment option, although the precise mechanism of action of the compound remains unclear.

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Nitroxides as Antioxidants and Anticancer Drugs

Cited by 102 publications

References 134 publications

Detection of Superoxide Alterations Induced by 5-Fluorouracil on HeLa Cells with a Cell-Based Biosensor

Detection of Superoxide Alterations Induced by 5-Fluorouracil on HeLa Cells with a Cell-Based Biosensor

It takes two for chronic wounds to heal: dispersing bacterial biofilm and modulating inflammation with dual action plasma coatings

Nitroxides Mitigate Neutrophil-Mediated Damage to the Myocardium after Experimental Myocardial Infarction in Rats

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