Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate

Tovmasyan, Artak; Bueno-Janice, Jacqueline C.; Jaramillo, Melba C.; Sampaio, Rômulo Severo; Rebouças, Júlio S.; Kyui, Natalia; Benov, Ludmil; Deng, Brian; Huang, Ting; Tome, Margaret E.; Spasojević, Ivan; Batinić‐Haberle, Ines

doi:10.1089/ars.2017.7218

Cited by 35 publications

(95 citation statements)

References 64 publications

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“…While MnTnHex-2-PyP 5+ is a potent SOD mimetic, most recent studies point to its role and role of its porphyrin analogs (MnTE-2-PyP 5+ and MnTnBuOE-2-PyP 5+ ) in the modification of the activity of transcription factors including nuclear factor kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) [ 22 , 43 , 44 , 45 , 46 ] and different mitogen-activated protein kinases, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38-MAPK) [ 8 , 45 , 47 ]. Several studies provided evidence that this and other potent cationic porphyrin-based SOD mimics (such as MnTE-2-PyP 5+ and MnTnBuOE-2-PyP 5+ ) modify protein cysteines of transcription factors [ 44 , 45 , 46 ], MAPK, and protein phosphatase 2A through their S-glutathionylation, thereby modifying their activities [ 45 , 47 ]. We have provided the evidence and the mechanistic basis that the SOD-like potency of Mn porphyrins is proportional to their ability to S -glutathionylate cysteines of proteins [ 6 , 29 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

et al. 2018

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Radiation injury to the lung is the result of acute and chronic free radical formation, and there are currently few effective means of mitigating such injury. Studies in rodents indicate that superoxide dismutase mimetics may be effective in this regard; however, studies in humans or large animals are lacking. We hypothesized that post-exposure treatment with the lipophilic mitochondrial superoxide dismutase mimetic, MnTnHex-2-PyP5+ (hexyl), would reduce radiation-induced pneumonitis and fibrosis in the lungs of nonhuman primates. Rhesus monkeys (Macaca mulatta) received 10 Gy whole thorax irradiation, 10 Gy + hexyl treatment, sham irradiation, or sham irradiation + hexyl. Hexyl was given twice daily, subcutaneously, at 0.05 mg/kg, for 2 months. Animals were monitored daily, and respiratory rates, pulse oximetry, hematology and serum chemistry panels were performed weekly. Computed tomography scans were performed at 0, 2, and 4 months after irradiation. Supportive fluid therapy, corticosteroids, analgesics, and antibiotics were given as needed. All animals were humanely euthanized 4.5 months after irradiation, and pathologic assessments were made. Multifocal, progressive lung lesions were seen at 2 and 4 months in both irradiated groups. Hexyl treatment delayed the onset of radiation-induced lung lesions, reduced elevations of respiratory rate, and reduced pathologic increases in lung weight. No adverse effects of hexyl treatment were found. These results demonstrate (1) development of a nonhuman primate model of radiation-induced lung injury, (2) a significant mitigating effect of hexyl treatment on lung pathology in this model, and (3) no evidence for toxicity of hexyl at the dose studied.

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Section: Introductionmentioning

confidence: 99%

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

et al. 2018

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“…A well known therapeutic attribute of MnPs is their ability to protect healthy cells and increase susceptibility of malignant cells to radiation therapy. This process has been attributed in part to increased H 2 O 2 which, in a process catalyzed by MnP, oxidizes signaling proteins such as NFκB [4,10,31]. Our results suggest that persulfides produced by MnP oxidation of H 2 S could have a similar effect with the added bonus of direct oxidant scavenging by persulfides.…”

Section: Antioxidant Function Of Mnp-generated Polysulfidesmentioning

confidence: 64%

“…As shown in Figure 6A,B, MnTE decreased H 2 S and increased polysulfides in both cell lines consistent with previous observations (cf. Figures 1 and 5 The biological actions of MnPs are thought to be due to redox cycling where oxidized Mn(III)P is reduced by a reductant such as ascorbic acid (AA) and then re-oxidized by oxygen which generates superoxide [4,[8][9][10]. The superoxide then spontaneously (or catalyzed by SOD or MnPs if present) dismutes to form peroxide and oxygen with the ultimate biological effects exerted by the peroxide.…”

Section: Effects Of Ascorbic Acid On Mnte Oxidation Of H 2 S In Hek Amentioning

confidence: 99%

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism

et al. 2020

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Manganese porphyrins (MnPs), MnTE-2-PyP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are superoxide dismutase (SOD) mimetics and form a redox cycle between O2 and reductants, including ascorbic acid, ultimately producing hydrogen peroxide (H2O2). We previously found that MnPs oxidize hydrogen sulfide (H2S) to polysulfides (PS; H2Sn, n = 2–6) in buffer. Here, we examine the effects of MnPs for 24 h on H2S metabolism and PS production in HEK293, A549, HT29 and bone marrow derived stem cells (BMDSC) using H2S (AzMC, MeRho-AZ) and PS (SSP4) fluorophores. All MnPs decreased intracellular H2S production and increased intracellular PS. H2S metabolism and PS production were unaffected by cellular O2 (5% versus 21% O2), H2O2 or ascorbic acid. We observed with confocal microscopy that mitochondria are a major site of H2S production in HEK293 cells and that MnPs decrease mitochondrial H2S production and increase PS in what appeared to be nucleoli and cytosolic fibrillary elements. This supports a role for MnPs in the metabolism of H2S to PS, the latter serving as both short- and long-term antioxidants, and suggests that some of the biological effects of MnPs may be attributable to sulfur metabolism.

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“…Efforts have been made in order to develop methodologies to assess tissue and subcellular distributions of MnP. One of the analytical methods reported involves subcellular fractionation, substitution of the porphyrin Mn(II) site with Zn(II), followed by fluorimetric detection and LC-MS/MS quantification (57)(58)(59). Previous studies on cell incorporation, have observed the effect of MnP on SOD-deficient bacteria and yeast, which grow very poorly in the presence of oxygen.…”

Section: Introductionmentioning

confidence: 99%

Manganese porphyrin redox state in endothelial cells: Resonance Raman studies and implications for antioxidant protection towards peroxynitrite

Carballal

Valez

Álvarez-Paggi

et al. 2018

Free Radical Biology and Medicine

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Cationic manganese(III) ortho N-substituted pyridylporphyrins (MnP) act as efficient antioxidants catalyzing superoxide dismutation and accelerating peroxynitrite reduction. Importantly, MnP can reach mitochondria offering protection against reactive species in different animal models of disease. Although an LC-MS/MS-based method for MnP quantitation and subcellular distribution has been reported, a direct method capable of evaluating both the uptake and the redox state of MnP in living cells has not yet been developed. In the present work we applied resonance Raman (RR) spectroscopy to analyze the intracellular accumulation of two potent MnP-based lipophilic SOD mimics, MnTnBuOE-2-PyP and MnTnHex-2-PyP within endothelial cells. RR experiments with isolated mitochondria revealed that the reduction of Mn(III)P was affected by inhibitors of the electron transport chain, supporting the action of MnP as efficient redox active compounds in mitochondria. Indeed, RR spectra confirmed that MnP added in the Mn(III) state can be incorporated into the cells, readily reduced by intracellular components to the Mn(II) state and oxidized by peroxynitrite. To assess the combined impact of reactivity and bioavailability, we studied the kinetics of Mn(III)TnBuOE-2-PyP with peroxynitrite and evaluated the cytoprotective capacity of MnP by exposing the endothelial cells to nitro-oxidative stress induced by peroxynitrite. We observed a preservation of normal mitochondrial function, attenuation of cell damage and prevention of apoptotic cell death. These data introduce a novel application of RR spectroscopy for the direct detection of MnP and their redox states inside living cells, and helps to rationalize their antioxidant capacity in biological systems.

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Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate

Abstract: The interplay between the accumulation of cationic MnPs and their potency as catalysts for oxidation of Asc, protein cysteines, and GSH controls the magnitude of their anticancer therapeutic effects.

Cited by 35 publications

References 64 publications

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism

Manganese porphyrin redox state in endothelial cells: Resonance Raman studies and implications for antioxidant protection towards peroxynitrite

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