scholarly journals High Potency of a Novel Resveratrol Derivative, 3,3′,4,4′-Tetrahydroxy-trans-stilbene, against Ovarian Cancer Is Associated with an Oxidative Stress-Mediated Imbalance between DNA Damage Accumulation and Repair

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Justyna Mikuła-Pietrasik ◽  
Patrycja Sosińska ◽  
Marek Murias ◽  
Marcin Wierzchowski ◽  
Marta Brewińska-Olchowik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
P38 Mapk ◽  
Cancer Cell ◽  
Damage Accumulation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Stress Dependent

We explored the effect of a new resveratrol (RVT) derivative, 3,3′,4,4′-tetrahydroxy-trans-stilbene (3,3′,4,4′-THS), on viability, apoptosis, proliferation, and senescence of three representative lines of ovarian cancer cells, that is, A2780, OVCAR-3, and SKOV-3,in vitro. In addition, the mechanistic aspects of 3,3′,4,4′-THS activity, including cell redox homeostasis (the production of reactive oxygen species, activity of enzymatic antioxidants, and magnitude of DNA damage accumulation and repair), and the activity of caspases (3, 8, and 9) and p38 MAPK were examined. The study showed that 3,3′,4,4′-THS affects cancer cell viability much more efficiently than its parent drug. This effect coincided with increased generation of reactive oxygen species, downregulated activity of superoxide dismutase and catalase, and excessive accumulation of 8-hydroxy-2′-deoxyguanosine and its insufficient repair due to decreased expression of DNA glycosylase I. Cytotoxicity elicited by 3,3′,4,4′-THS was related to increased incidence of apoptosis, which was mediated by caspases 3 and 9. Moreover, 3,3′,4,4′-THS inhibited cancer cell proliferation and accelerated senescence, which was accompanied by the activation of p38 MAPK. Collectively, our findings indicate that 3,3′,4,4′-THS may constitute a valuable tool in the fight against ovarian malignancy and that the anticancer capabilities of this stilbene proceed in an oxidative stress-dependent mechanism.

scholarly journals Niosome-carvedilol protects DNA damage of supraphysiologic concentrations of insulin using comet assay: An in vitro study

2021 ◽  
pp. 096032712110361
Author(s):  
Marzieh Farahani-Zangaraki ◽  
Azade Taheri ◽  
Mahmoud Etebari
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Comet Assay ◽  
Protective Effect ◽  
Reactive Oxygen ◽  
Diabetic Patients ◽  
Oxygen Species ◽  
Type 2 Diabetic Patients

Introduction: Hyperinsulinemia occurs in type 2 diabetic patients with insulin resistance. This increase in insulin levels in the blood increases reactive oxygen species production and oxidative stress, resulting in DNA damage. Carvedilol (CRV) is a non-selective beta-blocker, and research has shown that this compound and its metabolites have anti-oxidative properties. Carvedilol can, directly and indirectly, reduce reactive oxygen species (ROS) and has a protective effect on DNA damage from oxidative stress. Given the insolubility of CRV in water, finding new methods to increase its solubility can be an essential step in research. This study aimed to determine whether carvedilol could have a protective effect on insulin-induced genomic damage. Methods: We treated cells with insulin alone, amorphous-CRV alone, and amorphous-CRV and niosomal-CRV with insulin and DNA damage were investigated using the comet method to achieve this goal. Results: Our results showed that insulin in the studied concentration has a significant genotoxic effect and non-cytotoxic at higher concentrations. CRV, both in amorphous and niosome form, reduced insulin-induced DNA damage by reducing ROS production. The comet assay results demonstrate that treating HUVEC cells in pretreatment condition with amorphous-CRV and niosome-CRV significantly reduces DNA damage of insulin.

scholarly journals Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth

2021 ◽  
Vol 22 (4) ◽  
pp. 2088
Author(s):  
Rosalin Mishra ◽  
Long Yuan ◽  
Hima Patel ◽  
Aniruddha S. Karve ◽  
Haizhou Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Cell Growth ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cancer Cell Growth ◽  
Damage Response

RIDR-PI-103 is a novel reactive oxygen species (ROS)-induced drug release prodrug with a self-cyclizing moiety linked to a pan-PI3K inhibitor (PI-103). Under high ROS, PI-103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR-PI-103 in breast cancer remains unexplored. Cell viability of RIDR-PI-103 was assessed on breast cancer cells (MDA-MB-231, MDA-MB-361 and MDA-MB-453), non-tumorigenic MCF10A and fibroblasts. Matrigel colony formation, cell proliferation and migration assays examined the migratory properties of breast cancers upon treatment with RIDR-PI-103 and doxorubicin. Western blots determined the effect of doxorubicin ± RIDR-PI-103 on AKT activation and DNA damage response. Pharmacokinetic (PK) studies using C57BL/6J mice determined systemic exposure (plasma concentrations and overall area under the curve) and T1/2 of RIDR-PI-103. MDA-MB-453, MDA-MB-231 and MDA-MB-361 cells were sensitive to RIDR-PI-103 vs. MCF10A and normal fibroblast. Combination of doxorubicin and RIDR-PI-103 suppressed cancer cell growth and proliferation. Doxorubicin with RIDR-PI-103 inhibited p-AktS473, upregulated p-CHK1/2 and p-P53. PK studies showed that ~200 ng/mL (0.43 µM) RIDR-PI-103 is achievable in mice plasma with an initial dose of 20 mg/kg and a 10 h T1/2. (4) The prodrug RIDR-PI-103 could be a potential therapeutic for treatment of breast cancer patients.

scholarly journals The p66Shc protein controls redox signaling and oxidation-dependent DNA damage in human liver cells

2015 ◽  
Vol 309 (10) ◽  
pp. G826-G840 ◽  
Author(s):  
Sebastio Perrini ◽  
Federica Tortosa ◽  
Annalisa Natalicchio ◽  
Consiglia Pacelli ◽  
Angelo Cignarelli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Hepg2 Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Protein Levels ◽  
Human Liver Cells ◽  
Alcoholic Steatohepatitis ◽  
Liver Biopsies

The p66Shc protein mediates oxidative stress-related injury in multiple tissues. Steatohepatitis is characterized by enhanced oxidative stress-mediated cell damage. The role of p66Shc in redox signaling was investigated in human liver cells and alcoholic steatohepatitis. HepG2 cells with overexpression of wild-type or mutant p66Shc, with Ser36 replacement by Ala, were obtained through infection with recombinant adenoviruses. Reactive oxygen species and oxidation-dependent DNA damage were assessed by measuring dihydroethidium oxidation and 8-hydroxy-2′-deoxyguanosine accumulation into DNA, respectively. mRNA and protein levels of signaling intermediates were evaluated in HepG2 cells and liver biopsies from control and alcoholic steatohepatitis subjects. Exposure to H2O2 increased reactive oxygen species and phosphorylation of p66Shc on Ser36 in HepG2 cells. Overexpression of p66Shc promoted reactive oxygen species synthesis and oxidation-dependent DNA damage, which were further enhanced by H2O2. p66Shc activation also resulted in increased Erk-1/2, Akt, and FoxO3a phosphorylation. Blocking of Erk-1/2 activation inhibited p66Shc phosphorylation on Ser36. Increased p66Shc expression was associated with reduced mRNA levels of antioxidant molecules, such as NF-E2-related factor 2 and its target genes. In contrast, overexpression of the phosphorylation defective p66Shc Ala36 mutant inhibited p66Shc signaling, enhanced antioxidant genes, and suppressed reactive oxygen species and oxidation-dependent DNA damage. Increased p66Shc protein levels and Akt phosphorylation were observed in liver biopsies from alcoholic steatohepatitis compared with control subjects. In human alcoholic steatohepatitis, increased hepatocyte p66Shc protein levels may enhance susceptibility to DNA damage by oxidative stress by promoting reactive oxygen species synthesis and repressing antioxidant pathways.

SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging

2012 ◽  
Vol 444 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Albert Giralt ◽  
Francesc Villarroya
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Energy Metabolism ◽  
Reactive Oxygen ◽  
Acetate Metabolism ◽  
Oxygen Species ◽  
Neural Degeneration ◽  
The Metabolic Syndrome ◽  
Brown Adipose ◽  
Stress Dependent

SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress-related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration.

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