“Redox Imaging” to Distinguish Cells with Different Proliferative Indexes: Superoxide, Hydroperoxides, and Their Ratio as Potential Biomarkers

Zhelev, Zhivko; Georgieva, Ekaterina; Lazarova, Dessislava; Semkova, Severina; Aoki, Ichio; Gulubova, Maya; Higashi, Tatsuya; Bakalova, Rumiana

doi:10.1155/2019/6373685

Cited by 8 publications

(9 citation statements)

References 61 publications

(105 reference statements)

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“…Both probes penetrate the cells and localize mainly in the mitochondria [ 71 , 72 ]. Signals from the probes are not detected in the absence of superoxide, but are detectable after their interaction with superoxide, which was visualized by the appearance of fluorescence signal (in the presence of MitoSOX) or EPR signal (in the presence of mito-TEMPOH) in the cell suspensions [ 71 , 72 , 85 , 86 ].…”

Section: Resultsmentioning

confidence: 99%

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Bakalova

Semkova

Ivanova

et al. 2020

Oxidative Medicine and Cellular Longevity

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Redox-active substances and their combinations, such as of quinone/ascorbate and in particular menadione/ascorbate (M/A; also named Apatone®), attract attention with their unusual ability to kill cancer cells without affecting the viability of normal cells as well as with the synergistic anticancer effect of both molecules. So far, the primary mechanism of M/A-mediated anticancer effects has not been linked to the mitochondria. The aim of our study was to clarify whether this “combination drug” affects mitochondrial functionality specifically in cancer cells. Studies were conducted on cancer cells (Jurkat, Colon26, and MCF7) and normal cells (normal lymphocytes, FHC, and MCF10A), treated with different concentrations of menadione, ascorbate, and/or their combination (2/200, 3/300, 5/500, 10/1000, and 20/2000 μM/μM of M/A). M/A exhibited highly specific and synergistic suppression on cancer cell growth but without adversely affecting the viability of normal cells at pharmacologically attainable concentrations. In M/A-treated cancer cells, the cytostatic/cytotoxic effect is accompanied by (i) extremely high production of mitochondrial superoxide (up to 15-fold over the control level), (ii) a significant decrease of mitochondrial membrane potential, (iii) a decrease of the steady-state levels of ATP, succinate, NADH, and NAD+, and (iv) a decreased expression of programed cell death ligand 1 (PD-L1)—one of the major immune checkpoints. These effects were dose dependent. The inhibition of NQO1 by dicoumarol increased mitochondrial superoxide and sensitized cancer cells to M/A. In normal cells, M/A induced relatively low and dose-independent increase of mitochondrial superoxide and mild oxidative stress, which seems to be well tolerated. These data suggest that all anticancer effects of M/A result from a specific mechanism, tightly connected to the mitochondria of cancer cells. At low/tolerable doses of M/A (1/100-3/300 μM/μM) attainable in cancer by oral and parenteral administration, M/A sensitized cancer cells to conventional anticancer drugs, exhibiting synergistic or additive cytotoxicity accompanied by impressive induction of apoptosis. Combinations of M/A with 13 anticancer drugs were investigated (ABT-737, barasertib, bleomycin, BEZ-235, bortezomib, cisplatin, everolimus, lomustine, lonafarnib, MG-132, MLN-2238, palbociclib, and PI-103). Low/tolerable doses of M/A did not induce irreversible cytotoxicity in cancer cells but did cause irreversible metabolic changes, including: (i) a decrease of succinate and NADH, (ii) depolarization of the mitochondrial membrane, and (iii) overproduction of superoxide in the mitochondria of cancer cells only. In addition, M/A suppressed tumor growth in vivo after oral administration in mice with melanoma and the drug downregulated PD-L1 in melanoma cells. Experimental data suggest a great potential for beneficial anticancer effects of M/A through increasing the sensitivity of cancer cells to conventional anticancer therapy, as well as to the immune system, while sparing normal cells. We hypothesize that M/A-mediated anticancer effects are triggered by redox cycling of both substances, specifically within dysfunctional mitochondria. M/A may also have a beneficial effect on the immune system, making cancer cells “visible” and more vulnerable to the native immune response.

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Section: Resultsmentioning

confidence: 99%

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Bakalova

Semkova

Ivanova

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…It should be noted that SLENU was the most appropriate nitroxyl probe to evaluate tissue redox status in vivo due to its easy intracellular delivery and prolonged retention in the tissues. In addition, our recent EPR study on cultured cells with different proliferative indexes demonstrated that EPR signal decay is well correlated with proliferating activity ( 199 ). The slowest rate of EPR signal attenuation was detected in rapidly proliferating cancer cells, with a higher rate in slowly proliferating noncancer cells and the highest rate in nonproliferating cells.…”

Section: Nitroxyl Radical Contrast Agent For Imaging Redox Imbalance and Oxidative Stress In Living Biological Subjectsmentioning

confidence: 99%

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging

Matsumoto

Nakanishi

Zhelev

et al. 2022

Antioxidants & Redox Signaling

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Significance: In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy. Recent Advances: In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics. Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed. Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redoxsensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress. Antioxid. Redox Signal. 00, 000-000.

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“…High cholesterol diet induced redox-imbalance in kidney was visualized using MRI and mito-TEMPO as a contrast [ 105 ]. EPR spectroscopic analysis in cells using several type of nitroxyl radical probes would be important to validate the phenomenon observed by MR redox imaging [ 106 ].…”

Section: Imaging Tissue Redox Status (Redox Imaging) Using Redox Smentioning

confidence: 99%

Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI, EPRI, and PET

Matsumoto¹,

Mitchell

Krishna

2021

Molecules

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Radiation therapy is one of the main modalities to treat cancer/tumor. The response to radiation therapy, however, can be influenced by physiological and/or pathological conditions in the target tissues, especially by the low partial oxygen pressure and altered redox status in cancer/tumor tissues. Visualizing such cancer/tumor patho-physiological microenvironment would be a useful not only for planning radiotherapy but also to detect cancer/tumor in an earlier stage. Tumor hypoxia could be sensed by positron emission tomography (PET), electron paramagnetic resonance (EPR) oxygen mapping, and in vivo dynamic nuclear polarization (DNP) MRI. Tissue oxygenation could be visualized on a real-time basis by blood oxygen level dependent (BOLD) and/or tissue oxygen level dependent (TOLD) MRI signal. EPR imaging (EPRI) and/or T1-weighted MRI techniques can visualize tissue redox status non-invasively based on paramagnetic and diamagnetic conversions of nitroxyl radical contrast agent. 13C-DNP MRI can visualize glycometabolism of tumor/cancer tissues. Accurate co-registration of those multimodal images could make mechanisms of drug and/or relation of resulted biological effects clear. A multimodal instrument, such as PET-MRI, may have another possibility to link multiple functions. Functional imaging techniques individually developed to date have been converged on the concept of theranostics.

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“Redox Imaging” to Distinguish Cells with Different Proliferative Indexes: Superoxide, Hydroperoxides, and Their Ratio as Potential Biomarkers

Cited by 8 publications

References 61 publications

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging

Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI, EPRI, and PET

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