Abstract:
:Reactivation of p53 and induction of tumor cell apoptosis (RITA) is a small molecule that blocks p53-MDM2 interaction, thereby reactivating p53 in tumors. RITA can induce exclusive apoptosis in cancer cells independently of the p53 pathway; however, the resistance of cancer cells remains a major drawback. Here, we found a novel resistance mechanism of RITA treatment and an effective combined treatment to overcome RITA resistance in head and neck cancer (HNC) cells. The effects of RITA and 3-methyladenine (3-MA) were tested in different HNC cell lines, including cisplatin-resistant and acquired RITA-resistant HNC cells. The effects of each drug alone and in combination were assessed by measuring cell viability, apoptosis, cell cycle, glutathione, reactive oxygen species, protein expression, genetic inhibition of p62 and Nrf2, and a mouse xenograft model of cisplatin-resistant HNC. RITA induced apoptosis of HNC cells at different levels without significantly inhibiting normal cell viability. Following RITA treatment, RITA-resistant HNC cells exhibited a sustained expression of other autophagy-related proteins, overexpressed p62, and displayed activation of the Keap1-Nrf2 antioxidant pathway. The autophagy inhibitor 3-MA sensitized resistant HNC cells to RITA treatment via the dual inhibition of molecules related to the autophagy and antioxidant systems. Silencing of the p62 gene augmented the combined effects. The effective antitumor activity of RITA plus 3-MA was also confirmed in vivo in mouse xenograft models transplanted with resistant HNC cells, showing increased oxidative stress and DNA damage. The results indicate that RITA plus 3-MA can help overcome RITA resistance in HNC cells. CONDENSED ABSTRACT:This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo.
journal_name
Redox Bioljournal_title
Redox biologyauthors
Shin D,Kim EH,Lee J,Roh JLdoi
10.1016/j.redox.2017.05.025subject
Has Abstractpub_date
2017-10-01 00:00:00pages
219-227issn
2213-2317pii
S2213-2317(17)30343-9journal_volume
13pub_type
杂志文章相关文献
Redox Biology文献大全abstract::Transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), control the redox and metabolic homeostasis and oxidative stress. Inhibitors of Keap1-Nrf2 interaction are promising in oxidative stress related inflamm...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101565
更新日期:2020-07-01 00:00:00
abstract::Disulfide bonds play a key function in determining the structure of proteins, and are the most strongly conserved compositional feature across proteomes. They are particularly common in extracellular environments, such as the extracellular matrix and plasma, and in proteins that have structural (e.g. matrix) or bindin...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101822
更新日期:2021-01-01 00:00:00
abstract::Oxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this c...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2015.11.011
更新日期:2016-04-01 00:00:00
abstract::The generation of excessive amounts of reactive oxygen species (ROS) leads to cellular oxidative stress that underlies a variety of forms of hepatocyte injury and death including that from alcohol. Although ROS can induce cell damage through direct effects on cellular macromolecules, the injurious effects of ROS are m...
journal_title:Redox biology
pub_type: 杂志文章,评审
doi:10.1016/j.redox.2014.09.004
更新日期:2014-01-01 00:00:00
abstract::Retinal tissue receives its supply of oxygen from two sources - the retinal and choroidal circulations. Decreases in retinal blood flow occur in the early stages of diabetes, with the eventual development of hypoxia thought to contribute to pathological neovascularization. Oxygen consumption in the retina has been fou...
journal_title:Redox biology
pub_type: 杂志文章,评审
doi:10.1016/j.redox.2014.04.006
更新日期:2014-04-18 00:00:00
abstract:BACKGROUND:The Ras family of small GTPases cycle between an inactive, GDP-bound state and an active, GTP-bound state. When bound to GTP, Ras engages and activates a number of effectors that mediate proliferative and survival signals. Ras is mutated in over 30% of human cancers, usually at codons 12, 13, or 61, to remai...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2015.09.015
更新日期:2015-08-01 00:00:00
abstract::Mitochondria are critical sources of hydrogen peroxide (H2O2), an important secondary messenger in mammalian cells. Recent work has shown that O2•-/H2O2 emission from individual sites of production in mitochondria is regulated by protein S-glutathionylation. Here, we conducted the first examination of O2•-/H2O2 releas...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2017.12.006
更新日期:2018-05-01 00:00:00
abstract::It has been shown that anti-inflammatory cytokines interleukin-35 (IL-35) and IL-10 could inhibit acute endothelial cell (EC) activation, however, it remains unknown if and by what pathways IL-35 and IL-10 could block atherogenic lipid lysophosphatidylcholine (LPC)-induced sustained EC activation; and if mitochondrial...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2019.101373
更新日期:2020-01-01 00:00:00
abstract::In this paper, we describe an assay to analyze simultaneously the oxygen consumption rate (OCR) and superoxide production in a biological system. The analytical set-up uses electron paramagnetic resonance (EPR) spectroscopy with two different isotopically-labelled sensors: 15N-PDT (4-oxo-2,2,6,6-tetramethylpiperidine-...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101852
更新日期:2020-12-28 00:00:00
abstract::The system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2017.12.008
更新日期:2018-05-01 00:00:00
abstract::Microglia-mediated neuroinflammation plays a crucial role in the pathophysiological process of multiple neurological disorders such as ischemic stroke, yet lacks effective therapeutic agents. Previously, we discovered one novel synthetic compound, tanshinol borneol ester (DBZ), possesses anti-inflammatory and anti-ath...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101644
更新日期:2020-09-01 00:00:00
abstract::Glutathione peroxidase 2 (GPx2) is one of the five selenoprotein GPxs having a selenocysteine in the active center. GPx2 is strongly expressed in the gastrointestinal epithelium, as is another isoform, GPx1, though with a different localization pattern. Both GPxs are redox-active enzymes that are important for the red...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2019.101388
更新日期:2020-01-01 00:00:00
abstract::Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and c...
journal_title:Redox biology
pub_type: 杂志文章,评审
doi:10.1016/j.redox.2020.101454
更新日期:2020-08-01 00:00:00
abstract::Mitochondria are often regarded as a major source of reactive oxygen species (ROS) in animal cells, with H2O2 being the predominant ROS released from mitochondria; however, it has been recently demonstrated that energized brain mitochondria may act as stabilizers of H2O2 concentration (Starkov et al. [1]) based on the...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2015.05.001
更新日期:2015-08-01 00:00:00
abstract::Redox signaling and oxidative stress are associated with tissue fibrosis and aging. Aging is recognized as a major risk factor for fibrotic diseases involving multiple organ systems, including that of the lung. A number of oxidant generating enzymes are upregulated while antioxidant defenses are deficient with aging a...
journal_title:Redox biology
pub_type: 杂志文章,评审
doi:10.1016/j.redox.2016.06.005
更新日期:2016-10-01 00:00:00
abstract::We previously reported that the highly reactive cell-free heme (CFH) is increased in the plasma of patients with chronic lung injury and causes pulmonary edema in animal model of acute respiratory distress syndrome (ARDS) post inhalation of halogen gas. However, the mechanisms by which CFH causes pulmonary edema are u...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101592
更新日期:2020-09-01 00:00:00
abstract::Matcha and green tea catechins such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC) and (-)-epigallocatechin gallate (EGCG) have long been studied for their antioxidant and health-promoting effects. Using specific fluorophores for H2S (AzMC) and polysulfides (SSP4) as well as IC-MS and UPLC-MS/MS-based techniques ...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101731
更新日期:2020-10-01 00:00:00
abstract::Divalent copper and iron cations have been acknowledged for their catalytic roles in physiological processes critical for homeostasis maintenance. Being redox-active, these metals act as cofactors in the enzymatic reactions of electron transfer. However, under pathophysiological conditions, owing to their high redox p...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101566
更新日期:2020-07-01 00:00:00
abstract::Superoxide dismutase (SOD) is known to be protective against oxidative stress-mediated skin dysfunction. Here we explore the potential therapeutic activities of RM191A, a novel SOD mimetic, on skin. RM191A is a water-soluble dimeric copper (Cu2+-Cu3+)-centred polyglycine coordination complex. It displays 10-fold highe...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101790
更新日期:2021-01-01 00:00:00
abstract::Selenium-binding protein 1 (SELENBP1) has recently been reported to catalyse the oxidation of methanethiol, an organosulfur compound produced by gut microbiota. Two of the reaction products of methanethiol oxidation, hydrogen peroxide and hydrogen sulphide, serve as signalling molecules for cell differentiation. Indee...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2018.11.004
更新日期:2019-01-01 00:00:00
abstract::Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO2-OA) is an el...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2018.11.008
更新日期:2019-02-01 00:00:00
abstract::Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2018.07.025
更新日期:2018-10-01 00:00:00
abstract::NRF2 is a redox-responsive transcription factor that regulates expression of cytoprotective genes via its interaction with DNA sequences known as antioxidant response elements (AREs). NRF2 activity is induced by oxidative stress, but oxidative stress is not the only context in which NRF2 can be activated. Mutations th...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2018.07.026
更新日期:2018-10-01 00:00:00
abstract::Nitric oxide (NO) inhibits cell respiration reversibly and in competition with O2 through the inhibition of the mitochondrial cytochrome c oxidase (Complex IV). At concentrations lower than those required to inhibit respiration, endogenous NO enhances the reduction of the electron transport chain, thus enabling cells ...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2015.09.034
更新日期:2015-08-01 00:00:00
abstract::Red blood cells (RBC) have been considered almost exclusively as a transporter of metabolic gases and nutrients for the tissues. It is an accepted dogma that RBCs take up and inactivate endothelium-derived NO via rapid reaction with oxyhemoglobin to form methemoglobin and nitrate, thereby limiting NO available for vas...
journal_title:Redox biology
pub_type: 杂志文章,评审
doi:10.1016/j.redox.2013.12.027
更新日期:2014-01-09 00:00:00
abstract::Glucose starvation is one of the major forms of metabolic stress in cancer cells. Deprivation of glucose impairs glycolysis and the pentose phosphate pathway, which elicits oxidative stress due to enhanced production of reactive oxygen species (ROS) and impaired antioxidant system, leading to redox imbalance and cell ...
journal_title:Redox biology
pub_type: 杂志文章,评审
doi:10.1016/j.redox.2019.101154
更新日期:2019-07-01 00:00:00
abstract::Keloids exhibit metabolic reprogramming including enhanced glycolysis and attenuated oxidative phosphorylation. Hypoxia induces a series of protective responses in mammalian cells. However, the metabolic phenotype of keloid fibroblasts under hypoxic conditions remains to be elucidated. The present study aimed to inves...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2020.101815
更新日期:2021-01-01 00:00:00
abstract::Hydrogen sulfide (H2S) is a gaseous signalling molecule involved in many physiological and pathological processes. There is increasing evidence that H2S is implicated in aging and lifespan control in the diet-induced longevity models. However, blood sulfide concentration of naturally long-lived species is not known. H...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2016.01.008
更新日期:2016-08-01 00:00:00
abstract::Oxidative stress and neuronal apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2018.09.022
更新日期:2019-01-01 00:00:00
abstract::Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced ...
journal_title:Redox biology
pub_type: 杂志文章
doi:10.1016/j.redox.2014.12.008
更新日期:2015-01-01 00:00:00