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Redox Active Molecules in Cancer Treatments

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 54177

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Special Issue Editors


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Guest Editor
Rudjer Bosković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
Interests: redox active compounds; anticancer treatment; chemoprevention; natural products and derivatives

E-Mail Website
Guest Editor
Charles University, Prague Praha, Czech Republic
Interests: synthesis of low-molecular potential drugs, computational chemistry, structure-activity relationships, antioxidants

Special Issue Information

Dear Colleagues,

The primary purpose of this Special Issue of Molecules is to present the results of in vitro, in vivo, and/or in silico studies of the biological effects and activities of the redox-active compounds observed in original research studies or collected and discussed in review articles.

It is already accepted that the change of cells' redox status changes their biological setup [[i]]. Accumulation of reactive oxygen species (ROS) leads to oxidative stress and, consequently, activation of redox-sensitive transcription factors, signalling and metabolic pathways, and orchestrated cell death. Antioxidants like some polyphenols, vitamin C, beta carotenes and glutathione have mostly been investigated because of their chemopreventive capabilities and direct and indirect ROS scavenging effects [[ii],[iii],[iv]]. However, recently the interest in pro-oxidant compounds has increased in association with the promotion of regulated death of cancer cells or with the development of novel anticancer approaches based on the selective inhibition of sustained NRF2/KEAP1 pathway in the cancer cells [[v],[vi]].

We would like to you invite to publish in this Special Issue data from original research studies or reviews focusing on chemical and pharmacological aspects of natural and (semi)synthetic molecules that change cellular ROS concentration and can exert antioxidant and/or pro-oxidant cellular effects. Topics include but are not limited to:

  • synthesis and modification of small molecular weight redox modulators with potential pharmacological applications, and the optimization of their antioxidant /pro-oxidant properties and ADMET profile
  • non-radical targeted scavenging mechanisms of action of redox modulators such as modulators of activities or/and transcription of glutathione peroxidases, catalase, glutathione-S-transferases and superoxide dismutases as well as KEAP1-NRF2 pathway
  • antioxidants with chemopreventive effects
  • compounds capable of modifying ROS levels and potentiating the effect of anticancer drugs
  • molecular sensitizers used in cancer therapy
  • redox-active compound affecting regulated cell deaths

[i]. Buettner, G.R.; Wagner, B.A.; Rodgers V.G. Quantitative redox biology: An approach to understand the role of reactive species in defining the cellular redox environment. Cell Biochem. Biophys. 2013, 67(2), 477-483. doi:10.1007/s12013-011-9320-3

[ii]. Stepanić V, Čipak Gašparović A, Gall Trošelj K, Amić D, Žarković N. Selected attributes of polyphenols in targeting oxidative stress in cancer. Curr. Top. Med. Chem. 2015, 15(5), 496-509. doi:10.2174/1568026615666150209123100

[iii]. Harej A, Macan Meščić A, Stepanić V, Klobučar M, Pavelić K, Pavelić Kraljević S, Raić-Malić S. The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives. Int. J. Mol. Sci. 2019, 20(19), 4735. doi:10.3390/ijms20194735

[iv]. Stepanić, V.; Matijašić, M.; Horvat, T.; Verbanac, D.; Kučerová-Chlupáčová, M.; Saso, L.; Žarković, N. Antioxidant Activities of Alkyl Substituted Pyrazine Derivatives of Chalcones—In Vitro and In Silico Study. Antioxidants 2019, 8, 90. doi:10.3390/antiox8040090

[v]. Perillo, B.; Di Donato, M.; Pezone, A.; Di Zazzo, E.; Giovannelli, P.; Galasso, G.; Castoria, G.; Migliaccio, A. ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med. 2020, 52(2), 192-203. doi:10.1038/s12276-020-0384-2.

[vi]. Panieri, E.; Buha, A.; Telkoparan-Akillilar, P.; Cevik, D.; Kouretas, D.; Veskoukis, A.; Skaperda, Z.; Tsatsakis, A.; Wallace, D.; Suzen, S.; Saso, L. Potential Applications of NRF2 Modulators in Cancer Therapy. Antioxidants 2020, 9(3), 193; doi:10.3390/antiox9030193

Dr. Višnja Stepanić
Dr. Marta Kučerová-Chlupáčová
Guest Editors

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Keywords

  • Antioxidants
  • Pro-oxidants
  • Gene transcription modulation
  • Signalling pathways modulation
  • Metabolic pathways modulation
  • Cancer therapy

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

2 pages, 212 KiB  
Editorial
Redox Active Molecules in Cancer Treatments
by Višnja Stepanić and Marta Kučerová-Chlupáčová
Molecules 2023, 28(3), 1485; https://doi.org/10.3390/molecules28031485 - 03 Feb 2023
Viewed by 933
Abstract
Cancer is one of the leading causes of death worldwide, with nearly 10 million deaths in 2020 [...] Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)

Research

Jump to: Editorial, Review

16 pages, 3315 KiB  
Article
Naringenin Induces ROS-Mediated ER Stress, Autophagy, and Apoptosis in Human Osteosarcoma Cell Lines
by Chiang-Wen Lee, Cathy Chia-Yu Huang, Miao-Ching Chi, Kuan-Han Lee, Kuo-Ti Peng, Mei-Ling Fang, Yao-Chang Chiang and Ju-Fang Liu
Molecules 2022, 27(2), 373; https://doi.org/10.3390/molecules27020373 - 07 Jan 2022
Cited by 14 | Viewed by 2570
Abstract
Osteosarcoma, a primary bone tumor, responds poorly to chemotherapy and radiation therapy in children and young adults; hence, as the basis for an alternative treatment, this study investigated the cytotoxic and antiproliferative effects of naringenin on osteosarcoma cell lines, HOS and U2OS, by [...] Read more.
Osteosarcoma, a primary bone tumor, responds poorly to chemotherapy and radiation therapy in children and young adults; hence, as the basis for an alternative treatment, this study investigated the cytotoxic and antiproliferative effects of naringenin on osteosarcoma cell lines, HOS and U2OS, by using cell counting kit-8 and colony formation assays. DNA fragmentation and the increase in the G2/M phase in HOS and U2OS cells upon treatment with various naringenin concentrations were determined by using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and Annexin V/propidium iodide double staining, respectively. Flow cytometry was performed, and 2′,7′-dichlorodihydrofluorescein diacetate, JC-1, and Fluo-4 AM ester probes were examined for reactive oxygen species (ROS) generation, mitochondrial membrane potential, and intracellular calcium levels, respectively. Caspase activation, cell cycle, cytosolic and mitochondrial, and autophagy-related proteins were determined using western blotting. The results indicated that naringenin significantly inhibited viability and proliferation of osteosarcoma cells in a dose-dependent manner. In addition, naringenin induced cell cycle arrest in osteosarcoma cells by inhibiting cyclin B1 and cyclin-dependent kinase 1 expression and upregulating p21 expression. Furthermore, naringenin significantly inhibited the growth of osteosarcoma cells by increasing the intracellular ROS level. Naringenin induced endoplasmic reticulum (ER) stress-mediated apoptosis through the upregulation of ER stress markers, GRP78 and GRP94. Naringenin caused acidic vesicular organelle formation and increased autophagolysosomes, microtubule-associated protein-light chain 3-II protein levels, and autophagy. The findings suggest that the induction of cell apoptosis, cell cycle arrest, and autophagy by naringenin through mitochondrial dysfunction, ROS production, and ER stress signaling pathways contribute to the antiproliferative effect of naringenin on osteosarcoma cells. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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21 pages, 4590 KiB  
Article
Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach
by Tsun-Thai Chai, Jiun-An Koh, Clara Chia-Ci Wong, Mohamad Zulkeflee Sabri and Fai-Chu Wong
Molecules 2021, 26(23), 7396; https://doi.org/10.3390/molecules26237396 - 06 Dec 2021
Cited by 12 | Viewed by 2789
Abstract
Some seed-derived antioxidant peptides are known to regulate cellular modulators of ROS production, including those proposed to be promising targets of anticancer therapy. Nevertheless, research in this direction is relatively slow owing to the inevitable time-consuming nature of wet-lab experimentations. To help expedite [...] Read more.
Some seed-derived antioxidant peptides are known to regulate cellular modulators of ROS production, including those proposed to be promising targets of anticancer therapy. Nevertheless, research in this direction is relatively slow owing to the inevitable time-consuming nature of wet-lab experimentations. To help expedite such explorations, we performed structure-based virtual screening on seed-derived antioxidant peptides in the literature for anticancer potential. The ability of the peptides to interact with myeloperoxidase, xanthine oxidase, Keap1, and p47phox was examined. We generated a virtual library of 677 peptides based on a database and literature search. Screening for anticancer potential, non-toxicity, non-allergenicity, non-hemolyticity narrowed down the collection to five candidates. Molecular docking found LYSPH as the most promising in targeting myeloperoxidase, xanthine oxidase, and Keap1, whereas PSYLNTPLL was the best candidate to bind stably to key residues in p47phox. Stability of the four peptide-target complexes was supported by molecular dynamics simulation. LYSPH and PSYLNTPLL were predicted to have cell- and blood-brain barrier penetrating potential, although intolerant to gastrointestinal digestion. Computational alanine scanning found tyrosine residues in both peptides as crucial to stable binding to the targets. Overall, LYSPH and PSYLNTPLL are two potential anticancer peptides that deserve deeper exploration in future. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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15 pages, 3838 KiB  
Article
The Implication of Low Dose Dimethyl Sulfoxide on Mitochondrial Function and Oxidative Damage in Cultured Cardiac and Cancer Cells
by Nonhlakanipho F. Sangweni, Phiwayinkosi V. Dludla, Nireshni Chellan, Lawrence Mabasa, Jyoti R. Sharma and Rabia Johnson
Molecules 2021, 26(23), 7305; https://doi.org/10.3390/molecules26237305 - 01 Dec 2021
Cited by 13 | Viewed by 4411
Abstract
Although numerous studies have demonstrated the biological and multifaceted nature of dimethyl sulfoxide (DMSO) across different in vitro models, the direct effect of “non-toxic” low DMSO doses on cardiac and cancer cells has not been clearly explored. In the present study, H9c2 cardiomyoblasts [...] Read more.
Although numerous studies have demonstrated the biological and multifaceted nature of dimethyl sulfoxide (DMSO) across different in vitro models, the direct effect of “non-toxic” low DMSO doses on cardiac and cancer cells has not been clearly explored. In the present study, H9c2 cardiomyoblasts and MCF-7 breast cancer cells were treated with varying concentrations of DMSO (0.001–3.7%) for 6 days. Here, DMSO doses < 0.5% enhanced the cardiomyoblasts respiratory control ratio and cellular viability relative to the control cells. However, 3.7% DMSO exposure enhanced the rate of apoptosis, which was driven by mitochondrial dysfunction and oxidative stress in the cardiomyoblasts. Additionally, in the cancer cells, DMSO (≥0.009) led to a reduction in the cell’s maximal respiratory capacity and ATP-linked respiration and turnover. As a result, the reduced bioenergetics accelerated ROS production whilst increasing early and late apoptosis in these cells. Surprisingly, 0.001% DMSO exposure led to a significant increase in the cancer cells proliferative activity. The latter, therefore, suggests that the use of DMSO, as a solvent or therapeutic compound, should be applied with caution in the cancer cells. Paradoxically, in the cardiomyoblasts, the application of DMSO (≤0.5%) demonstrated no cytotoxic or overt therapeutic benefits. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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12 pages, 2718 KiB  
Article
Cell Culture Characterization of Prooxidative Chain-Transfer Agents as Novel Cytostatic Drugs
by Victoria Heymans, Sascha Kunath, Parvana Hajieva and Bernd Moosmann
Molecules 2021, 26(21), 6743; https://doi.org/10.3390/molecules26216743 - 08 Nov 2021
Cited by 4 | Viewed by 2209
Abstract
Prooxidative therapy is a well-established concept in infectiology and parasitology, in which prooxidative drugs like artemisinin and metronidazole play a pivotal clinical role. Theoretical considerations and earlier studies have indicated that prooxidative therapy might also represent a promising strategy in oncology. Here, we [...] Read more.
Prooxidative therapy is a well-established concept in infectiology and parasitology, in which prooxidative drugs like artemisinin and metronidazole play a pivotal clinical role. Theoretical considerations and earlier studies have indicated that prooxidative therapy might also represent a promising strategy in oncology. Here, we have investigated a novel class of prooxidative drugs, namely chain-transfer agents, as cytostatic agents in a series of human tumor cell lines in vitro. We have found that different chain-transfer agents of the lipophilic thiol class (like dodecane-1-thiol) elicited half-maximal effective concentrations in the low micromolar range in SY5Y cells (human neuroblastoma), Hela cells (human cervical carcinoma), HEK293 cells (immortalized human kidney), MCF7 cells (human breast carcinoma), and C2C12 cells (mouse myoblast). In contrast, HepG2 cells (human hepatocellular carcinoma) were resistant to toxicity, presumably through their high detoxification capacity for thiol groups. Cytotoxicity was undiminished by hypoxic culture conditions, but substantially lowered after cellular differentiation. Compared to four disparate, clinically used reference compounds in vitro (doxorubicin, actinomycin D, 5-fluorouracil, and hydroxyurea), chain-transfer agents emerged as comparably potent on a molar basis and on a maximum-effect basis. Our results indicate that chain-transfer agents possess a promising baseline profile as cytostatic drugs and should be explored further for anti-tumor chemotherapy. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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19 pages, 4923 KiB  
Article
In Vitro Effects of Papaverine on Cell Proliferation, Reactive Oxygen Species, and Cell Cycle Progression in Cancer Cells
by Daniella A. Gomes, Anna M. Joubert and Michelle H. Visagie
Molecules 2021, 26(21), 6388; https://doi.org/10.3390/molecules26216388 - 22 Oct 2021
Cited by 7 | Viewed by 2079
Abstract
Papaverine (PPV) is an alkaloid isolated from the Papaver somniferum. Research has shown that PPV inhibits proliferation. However, several questions remain regarding the effects of PPV in tumorigenic cells. In this study, the influence of PPV was investigated on the proliferation (spectrophotometry), [...] Read more.
Papaverine (PPV) is an alkaloid isolated from the Papaver somniferum. Research has shown that PPV inhibits proliferation. However, several questions remain regarding the effects of PPV in tumorigenic cells. In this study, the influence of PPV was investigated on the proliferation (spectrophotometry), morphology (light microscopy), oxidative stress (fluorescent microscopy), and cell cycle progression (flow cytometry) in MDA-MB-231, A549, and DU145 cell lines. Exposure to 150 μM PPV resulted in time- and dose-dependent antiproliferative activity with reduced cell growth to 56%, 53%, and 64% in the MDA-MB-231, A549, and DU145 cell lines, respectively. Light microscopy revealed that PPV exposure increased cellular protrusions in MDA-MB-231 and A549 cells to 34% and 23%. Hydrogen peroxide production increased to 1.04-, 1.02-, and 1.44-fold in PPV-treated MDA-MB-231, A549, and DU145 cells, respectively, compared to cells propagated in growth medium. Furthermore, exposure to PPV resulted in an increase of cells in the sub-G1 phase by 46% and endoreduplication by 10% compared to cells propagated in growth medium that presented with 2.8% cells in the sub-G1 phase and less than 1% in endoreduplication. The results of this study contribute to understanding of effects of PPV on cancer cell lines. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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12 pages, 5364 KiB  
Article
Intermediate Detection in the Casiopeina–Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction
by Lillian G. Ramírez-Palma, Adrián Espinoza-Guillén, Fabiola Nieto-Camacho, Alexis E. López-Guerra, Virginia Gómez-Vidales, Fernando Cortés-Guzmán and Lena Ruiz-Azuara
Molecules 2021, 26(19), 5729; https://doi.org/10.3390/molecules26195729 - 22 Sep 2021
Cited by 4 | Viewed by 2037
Abstract
A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown [...] Read more.
A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown that Casiopeina copper complexes caused a dramatic intracellular GSH drop, forming disulfide bonds and reducing CuII to CuI. Herein, through the determination of the [CuII]–SH bond before reduction, we present evidence of the adduct between cysteine and one Casiopeina as an intermediate in the cystine formation and as a model to understand the anticancer activity of copper complexes. Evidence of such an intermediate has never been presented before. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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15 pages, 4189 KiB  
Article
Antioxidant Activity of Bioactive Peptide Fractions from Germinated Soybeans Conjugated to Fe3O4 Nanoparticles by the Ugi Multicomponent Reaction
by Yarelys Elena Augusto-Jimenez, Marcela González-Montoya, Dany Naranjo-Feliciano, Daniel Uribe-Ramírez, Eliseo Cristiani-Urbina, Carlos Díaz-Águila, Hernani Yee-Madeira and Rosalva Mora-Escobedo
Molecules 2021, 26(19), 5726; https://doi.org/10.3390/molecules26195726 - 22 Sep 2021
Cited by 4 | Viewed by 2346
Abstract
The conjugation of biomolecules to magnetic nanoparticles has emerged as promising approach in biomedicine as the treatment of several diseases, such as cancer. In this study, conjugation of bioactive peptide fractions from germinated soybeans to magnetite nanoparticles was achieved. Different fractions of germinated [...] Read more.
The conjugation of biomolecules to magnetic nanoparticles has emerged as promising approach in biomedicine as the treatment of several diseases, such as cancer. In this study, conjugation of bioactive peptide fractions from germinated soybeans to magnetite nanoparticles was achieved. Different fractions of germinated soybean peptides (>10 kDa and 5–10 kDa) were for the first time conjugated to previously coated magnetite nanoparticles (with 3-aminopropyltriethoxysilane (APTES) and sodium citrate) by the Ugi four-component reaction. The crystallinity of the nanoparticles was corroborated by X-ray diffraction, while the particle size was determined by scanning transmission electron microscopy. The analyses were carried out using infrared and ultraviolet–visible spectroscopy, dynamic light scattering, and thermogravimetry, which confirmed the coating and functionalization of the magnetite nanoparticles and conjugation of different peptide fractions on their surfaces. The antioxidant activity of the conjugates was determined by the reducing power and hydroxyl radical scavenging activity. The nanoparticles synthesized represent promising materials, as they have found applications in bionanotechnology for enhanced treatment of diseases, such as cancer, due to a higher antioxidant capacity than that of fractions without conjugation. The highest antioxidant capacity was observed for a >10 kDa peptide fraction conjugated to the magnetite nanoparticles coated with APTES. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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14 pages, 4310 KiB  
Article
Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells
by Mohamed M. Tawfik, Nourhan Eissa, Fayez Althobaiti, Eman Fayad and Ali H. Abu Almaaty
Molecules 2021, 26(17), 5185; https://doi.org/10.3390/molecules26175185 - 26 Aug 2021
Cited by 12 | Viewed by 3295
Abstract
Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed [...] Read more.
Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 μg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors’ knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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11 pages, 11147 KiB  
Article
Effects of Combination Treatments with Astaxanthin-Loaded Microparticles and Pentoxifylline on Intracellular ROS and Radiosensitivity of J774A.1 Macrophages
by Eleonora Binatti, Gianni Zoccatelli, Francesca Zanoni, Giulia Donà, Federica Mainente and Roberto Chignola
Molecules 2021, 26(17), 5152; https://doi.org/10.3390/molecules26175152 - 25 Aug 2021
Cited by 8 | Viewed by 2339
Abstract
Radiation-induced fibrosis (RIF) is a serious, yet incurable, complication of external beam radiation therapy for the treatment of cancer. Macrophages are key cellular actors in RIF because of their ability to produce reactive oxidants, such as reactive oxygen species (ROS) and inflammatory cytokines [...] Read more.
Radiation-induced fibrosis (RIF) is a serious, yet incurable, complication of external beam radiation therapy for the treatment of cancer. Macrophages are key cellular actors in RIF because of their ability to produce reactive oxidants, such as reactive oxygen species (ROS) and inflammatory cytokines that, in turn, are the drivers of pro-fibrotic pathways. In a previous work, we showed that phagocytosis could be exploited to deliver the potent natural antioxidant astaxanthin specifically to macrophages. For this purpose, astaxanthin encapsulated into µm-sized protein particles could specifically target macrophages that can uptake the particles by phagocytosis. In these cells, astaxanthin microparticles significantly reduced intracellular ROS levels and the secretion of bioactive TGFβ and increased cell survival after radiation treatments. Here we show that pentoxifylline, a drug currently used for the treatment of muscle pain resulting from peripheral artery disease, amplifies the effects of astaxanthin microparticles on J774A.1 macrophages. Combination treatments with pentoxifylline and encapsulated astaxanthin might reduce the risk of RIF in cancer patients. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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17 pages, 3708 KiB  
Article
Melatonin Induces Autophagy via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress Pathway in Colorectal Cancer Cells
by Kian Chung Chok, Rhun Yian Koh, Ming Guan Ng, Pei Ying Ng and Soi Moi Chye
Molecules 2021, 26(16), 5038; https://doi.org/10.3390/molecules26165038 - 20 Aug 2021
Cited by 17 | Viewed by 4182
Abstract
Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, [...] Read more.
Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, and cell migration. In previous studies, melatonin has been shown to have an anticancer effect in multiple tumors, including CRC, but the underlying mechanisms of melatonin action on CRC have not been fully explored. Thus, in this study, we investigated the role of autophagy pathways in CRC cells treated with melatonin. In vitro CRC cell models, HT-29, SW48, and Caco-2, were treated with melatonin. CRC cell death, oxidative stress, and autophagic vacuoles formation were induced by melatonin in a dose-dependent manner. Several autophagy pathways were examined, including the endoplasmic reticulum (ER) stress, 5′–adenosine monophosphate-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. Our results showed that melatonin significantly induced autophagy via the ER stress pathway in CRC cells. In conclusion, melatonin demonstrated a potential as an anticancer drug for CRC. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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13 pages, 1916 KiB  
Communication
Antiproliferative Effect of Colonic Fermented Phenolic Compounds from Jaboticaba (Myrciaria trunciflora) Fruit Peel in a 3D Cell Model of Colorectal Cancer
by Paula Rossini Augusti, Andréia Quatrin, Renius Mello, Vivian Caetano Bochi, Eliseu Rodrigues, Inês D. Prazeres, Ana Catarina Macedo, Sheila Cristina Oliveira-Alves, Tatiana Emanuelli, Maria Rosário Bronze and Ana Teresa Serra
Molecules 2021, 26(15), 4469; https://doi.org/10.3390/molecules26154469 - 24 Jul 2021
Cited by 8 | Viewed by 2985
Abstract
Jaboticaba is a Brazilian native berry described as a rich source of phenolic compounds (PC) with health promoting effects. PC from jaboticaba peel powder (JPP) have low intestinal bio-accessibility and are catabolized by gut microbiota. However, the biological implication of PC-derived metabolites produced [...] Read more.
Jaboticaba is a Brazilian native berry described as a rich source of phenolic compounds (PC) with health promoting effects. PC from jaboticaba peel powder (JPP) have low intestinal bio-accessibility and are catabolized by gut microbiota. However, the biological implication of PC-derived metabolites produced during JPP digestion remains unclear. This study aimed to evaluate the antiproliferative effects of colonic fermented JPP (FJPP) in a 3D model of colorectal cancer (CRC) composed by HT29 spheroids. JPP samples fermented with human feces during 0, 2, 8, 24 or 48 h were incubated (10,000 µg mL−1) with spheroids, and cell viability was assessed after 72 h. Chemometric analyses (cluster and principal component analyses) were used to identify the main compounds responsible for the bioactive effect. The antiproliferative effect of FJPP in the CRC 3D model was increased between 8 h and 24 h of incubation, and this effect was associated with HHDP-digalloylglucose isomer and dihydroxyphenyl-γ-valerolactone. At 48 h of fermentation, the antiproliferative effect of FJPP was negligible, indicating that the presence of urolithins did not improve the bioactivity of JPP. These findings provide relevant knowledge on the role of colonic microbiota fermentation to generate active phenolic metabolites from JPP with positive impact on CRC. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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14 pages, 1833 KiB  
Article
Activity Guided Isolation of Phenolic Compositions from Anneslea fragrans Wall. and Their Cytoprotective Effect against Hydrogen Peroxide Induced Oxidative Stress in HepG2 Cells
by Shuyue He, Xiaoyan Cui, Afsar Khan, Yaping Liu, Yudan Wang, Qimin Cui, Tianrui Zhao, Jianxin Cao and Guiguang Cheng
Molecules 2021, 26(12), 3690; https://doi.org/10.3390/molecules26123690 - 17 Jun 2021
Cited by 14 | Viewed by 2338
Abstract
Anneslea fragrans Wall., commonly known as “Pangpo Tea”, is traditionally used as a folk medicine and healthy tea for the treatment of liver and intestine diseases. The aim of this study was to purify the antioxidative and cytoprotective polyphenols from A. fragrans leaves. [...] Read more.
Anneslea fragrans Wall., commonly known as “Pangpo Tea”, is traditionally used as a folk medicine and healthy tea for the treatment of liver and intestine diseases. The aim of this study was to purify the antioxidative and cytoprotective polyphenols from A. fragrans leaves. After fractionation with polar and nonpolar organic solvents, the fractions of aqueous ethanol extract were evaluated for their total phenolic (TPC) and flavonoid contents (TFC) and antioxidant activities (DPPH, ABTS, and FRAP assays). The n-butanol fraction (BF) showed the highest TPC and TFC with the strongest antioxidant activity. The bio-guided chromatography of BF led to the purification of six flavonoids (16) and one benzoquinolethanoid (7). The structures of these compounds were determined by NMR and MS techniques. Compound 6 had the strongest antioxidant capacity, which was followed by 5 and 2. The protective effect of the isolated compounds on hydrogen peroxide (H2O2)-induced oxidative stress in HepG2 cells revealed that the compounds 5 and 6 exhibited better protective effects by inhibiting ROS productions, having no significant difference with vitamin C (p > 0.05), whereas 6 showed the best anti-apoptosis activity. The results suggest that A. fragrans could serve as a valuable antioxidant phytochemical source for developing functional food and health nutraceutical products. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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13 pages, 19930 KiB  
Article
Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling
by Giedrė Valiulienė, Aida Vitkevičienė, Giedrė Skliutė, Veronika Borutinskaitė and Rūta Navakauskienė
Molecules 2021, 26(8), 2303; https://doi.org/10.3390/molecules26082303 - 15 Apr 2021
Cited by 11 | Viewed by 2813
Abstract
Metabolic landscape and sensitivity to apoptosis induction play a crucial role in acute myeloid leukemia (AML) resistance. Therefore, we investigated the effect of metformin, a medication that also acts as an inhibitor of oxidative phosphorylation (OXPHOS), and MCL-1 inhibitor S63845 in AML cell [...] Read more.
Metabolic landscape and sensitivity to apoptosis induction play a crucial role in acute myeloid leukemia (AML) resistance. Therefore, we investigated the effect of metformin, a medication that also acts as an inhibitor of oxidative phosphorylation (OXPHOS), and MCL-1 inhibitor S63845 in AML cell lines NB4, KG1 and chemoresistant KG1A cells. The impact of compounds was evaluated using fluorescence-based metabolic flux analysis, assessment of mitochondrial Δψ and cellular ROS, trypan blue exclusion, Annexin V-PI and XTT tests for cell death and cytotoxicity estimations, also RT-qPCR and Western blot for gene and protein expression. Treatment with metformin resulted in significant downregulation of OXPHOS; however, increase in glycolysis was observed in NB4 and KG1A cells. In contrast, treatment with S63845 slightly increased the rate of OXPHOS in KG1 and KG1A cells, although it profoundly diminished the rate of glycolysis. Generally, combined treatment had stronger inhibitory effects on cellular metabolism and ATP levels. Furthermore, results revealed that treatment with metformin, S63845 and their combinations induced apoptosis in AML cells. In addition, level of apoptotic cell death correlated with cellular ROS induction, as well as with downregulation of tumor suppressor protein MYC. In summary, we show that modulation of redox-stress could have a potential anticancer activity in AML cells. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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24 pages, 9522 KiB  
Article
Influence of Oxidative Stress on Time-Resolved Oxygen Detection by [Ru(Phen)3]2+ In Vivo and In Vitro
by Veronika Huntosova, Denis Horvath, Robert Seliga and Georges Wagnieres
Molecules 2021, 26(2), 485; https://doi.org/10.3390/molecules26020485 - 18 Jan 2021
Cited by 7 | Viewed by 2611
Abstract
Detection of tissue and cell oxygenation is of high importance in fundamental biological and in many medical applications, particularly for monitoring dysfunction in the early stages of cancer. Measurements of the luminescence lifetimes of molecular probes offer a very promising and non-invasive approach [...] Read more.
Detection of tissue and cell oxygenation is of high importance in fundamental biological and in many medical applications, particularly for monitoring dysfunction in the early stages of cancer. Measurements of the luminescence lifetimes of molecular probes offer a very promising and non-invasive approach to estimate tissue and cell oxygenation in vivo and in vitro. We optimized the evaluation of oxygen detection in vivo by [Ru(Phen)3]2+ in the chicken embryo chorioallantoic membrane model. Its luminescence lifetimes measured in the CAM were analyzed through hierarchical clustering. The detection of the tissue oxygenation at the oxidative stress conditions is still challenging. We applied simultaneous time-resolved recording of the mitochondrial probe MitoTrackerTM OrangeCMTMRos fluorescence and [Ru(Phen)3]2+ phosphorescence imaging in the intact cell without affecting the sensitivities of these molecular probes. [Ru(Phen)3]2+ was demonstrated to be suitable for in vitro detection of oxygen under various stress factors that mimic oxidative stress: other molecular sensors, H2O2, and curcumin-mediated photodynamic therapy in glioma cancer cells. Low phototoxicities of the molecular probes were finally observed. Our study offers a high potential for the application and generalization of tissue oxygenation as an innovative approach based on the similarities between interdependent biological influences. It is particularly suitable for therapeutic approaches targeting metabolic alterations as well as oxygen, glucose, or lipid deprivation. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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Review

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30 pages, 14061 KiB  
Review
Review and Chemoinformatic Analysis of Ferroptosis Modulators with a Focus on Natural Plant Products
by Višnja Stepanić and Marta Kučerová-Chlupáčová
Molecules 2023, 28(2), 475; https://doi.org/10.3390/molecules28020475 - 04 Jan 2023
Cited by 13 | Viewed by 3187
Abstract
Ferroptosis is a regular cell death pathway that has been proposed as a suitable therapeutic target in cancer and neurodegenerative diseases. Since its definition in 2012, a few hundred ferroptosis modulators have been reported. Based on a literature search, we collected a set [...] Read more.
Ferroptosis is a regular cell death pathway that has been proposed as a suitable therapeutic target in cancer and neurodegenerative diseases. Since its definition in 2012, a few hundred ferroptosis modulators have been reported. Based on a literature search, we collected a set of diverse ferroptosis modulators and analyzed them in terms of their structural features and physicochemical and drug-likeness properties. Ferroptosis modulators are mostly natural products or semisynthetic derivatives. In this review, we focused on the abundant subgroup of polyphenolic modulators, primarily phenylpropanoids. Many natural polyphenolic antioxidants have antiferroptotic activities acting through at least one of the following effects: ROS scavenging and/or iron chelation activities, increased GPX4 and NRF2 expression, and LOX inhibition. Some polyphenols are described as ferroptosis inducers acting through the generation of ROS, intracellular accumulation of iron (II), or the inhibition of GPX4. However, some molecules have a dual mode of action depending on the cell type (cancer versus neural cells) and the (micro)environment. The latter enables their successful use (e.g., apigenin, resveratrol, curcumin, and EGCG) in rationally designed, multifunctional nanoparticles that selectively target cancer cells through ferroptosis induction. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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14 pages, 1829 KiB  
Review
AQP3 and AQP5—Potential Regulators of Redox Status in Breast Cancer
by Lidija Milković and Ana Čipak Gašparović
Molecules 2021, 26(9), 2613; https://doi.org/10.3390/molecules26092613 - 29 Apr 2021
Cited by 15 | Viewed by 3309
Abstract
Breast cancer is still one of the leading causes of mortality in the female population. Despite the campaigns for early detection, the improvement in procedures and treatment, drastic improvement in survival rate is omitted. Discovery of aquaporins, at first described as cellular plumbing [...] Read more.
Breast cancer is still one of the leading causes of mortality in the female population. Despite the campaigns for early detection, the improvement in procedures and treatment, drastic improvement in survival rate is omitted. Discovery of aquaporins, at first described as cellular plumbing system, opened new insights in processes which contribute to cancer cell motility and proliferation. As we discover new pathways activated by aquaporins, the more we realize the complexity of biological processes and the necessity to fully understand the pathways affected by specific aquaporin in order to gain the desired outcome–remission of the disease. Among the 13 human aquaporins, AQP3 and AQP5 were shown to be significantly upregulated in breast cancer indicating their role in the development of this malignancy. Therefore, these two aquaporins will be discussed for their involvement in breast cancer development, regulation of oxidative stress and redox signalling pathways leading to possibly targeting them for new therapies. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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18 pages, 2546 KiB  
Review
Involvement of NRF2 in Breast Cancer and Possible Therapeutical Role of Polyphenols and Melatonin
by Alev Tascioglu Aliyev, Emiliano Panieri, Višnja Stepanić, Hande Gurer-Orhan and Luciano Saso
Molecules 2021, 26(7), 1853; https://doi.org/10.3390/molecules26071853 - 25 Mar 2021
Cited by 30 | Viewed by 4820
Abstract
Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to [...] Read more.
Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to neurodegenerative diseases and cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor and reported as one of the most important oxidative stress regulators. Due to its regulatory role in the expression of numerous cytoprotective genes involved in the antioxidant and anti-inflammatory responses, the modulation of NRF2 seems to be a promising approach in the prevention and treatment of cancer. Breast cancer is the prevalent type of tumor in women and is the leading cause of death among female cancers. Oxidative stress-related mechanisms are known to be involved in breast cancer, and therefore, NRF2 is considered to be beneficial in its prevention. However, its overactivation may lead to a negative clinical impact on breast cancer therapy by causing chemoresistance. Some known “oxidative stress modulators”, such as melatonin and polyphenols, are suggested to play an important role in the prevention and treatment of cancer, where the activation of NRF2 is reported as a possible underlying mechanism. In the present review, the potential involvement of oxidative stress and NRF2 in breast cancer will be reviewed, and the role of the NRF2 modulators—namely, polyphenols and melatonin—in the treatment of breast cancer will be discussed. Full article
(This article belongs to the Special Issue Redox Active Molecules in Cancer Treatments)
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