Oxidative Stress-mediated DNA Damage Research Articles

DNA repair pathways important for the survival of Escherichia coli to hydrogen peroxide mediated killing.

Escherichia coli exposed to 1-3mM hydrogen peroxide undergo killing which is designated as the mode-one killing which is a result of oxidative DNA damage. Oxidative stress mediated DNA damage can be repaired by various DNA repair pathways like base excision repair, nucleotide excision repair and homologous recombination repair. In this study we have investigated the role of multiple DNA repair pathways in survival to oxidative killing and assessed their relative importance. Results show that both nucleotide excision repair pathway as well as the RecF pathway of recombination repair are important for repair of the DNA damage caused by exposure to hydrogen peroxide. The study also provides the evidence that RecG helicase which is known for the resolution of Holliday junction intermediates plays a critical role in the survival of mode-one killing by peroxide. There is a severe impact on the survival of repair mutants when parameters like aeration and growth medium are changed. Low aeration and growth in minimal medium provide significant protection from the mode-one killing suggesting that under natural conditions Escherichia coli cells are likely to be protected from the oxidative stress mediated DNA damage.

Astaxanthin protects oxidative stress mediated DNA damage and enhances longevity in Saccharomyces cerevisiae.

Reactive oxygen species (ROS) have long been found to play an important role in oxidative mediated DNA damage. Fortunately, cells possess an antioxidant system that can neutralize ROS. However, oxidative stress occurs when antioxidants are overwhelmed by ROS or impaired antioxidant pathways. This study was carried out to find the protective effect of astaxanthin on the yeast DNA repair-deficient mutant cells under hydrogen peroxide stress. The results showed that astaxanthin enhances the percent cell growth of rad1∆, rad51∆, apn1∆, apn2∆ and ogg1∆ cells. Further, the spot test and colony-forming unit count results confirmed that astaxanthin protects DNA repair mutant cells from oxidative stress. The DNA binding property of astaxanthin studied by in silico and in vitro methods indicated that astaxanthin binds to the DNA in the major and minor groove, and that might protect DNA against oxidative stress induced by Fenton's reagent. The intracellular ROS, 8-OHdG level and the DNA fragmentation as measured by comet tail was reduced by astaxanthin under oxidative stress. Similarly, reduced nuclear fragmentation and chromatin condensation results suggest that astaxanthin might reduce apoptosis. Finally, we show that astaxanthin decreases the accumulation of mutation rate and enhances the longevity of DNA repair-deficient mutants' cells during a chronological lifespan.

Thymol as a critical component of Thymus vulgaris L. essential oil combats Pseudomonas aeruginosa by intercalating DNA and inactivating biofilm

Pseudomonas aeruginosa is a notoriously difficult pathogen to control with antibiotics and disinfectants. Thymus vulgaris L. essential oil (TEO) and thymol are useful for replacing synthetic bacteriostatic agents due to their broad-spectrum bactericidal properties. This study focuses on understanding the inhibitory effects of TEO and its major component against P. aeruginosa, and exploring the antibacterial mechanism from the perspectives of cell membrane destruction, DNA intercalation and biofilm prevention. Results indicate that thymol is the principal component in TEO, as confirmed by GC-MS analysis. TEO and thymol potently combat the planktonic P. aeruginosa and directly change the cell structure. P. aeruginosa cell membrane integrity is destroyed as evidenced by an increase in permeability of the inner and outer membranes and the leakage of intracellular biological macromolecules (DNA). Our study further confirms that the accumulation of intracellular ROS caused by TEO and thymol can result in oxidative stress-mediated DNA damage. Thymol intercalates in the P. aeruginosa genomic DNA to affect the normal function of DNA and even cause bacterial death. Moreover, TEO and thymol affect the biofilm formation and limit the bacterial swimming and swarming motilities. This study provides a potential approach for the development and utilization of natural essential oils and bioactive compunds as novel food additives in the food processing.

Withanolide C Inhibits Proliferation of Breast Cancer Cells via Oxidative Stress-Mediated Apoptosis and DNA Damage.

Some withanolides, particularly the family of steroidal lactones, show anticancer effects, but this is rarely reported for withanolide C (WHC)—especially anti-breast cancer effects. The subject of this study is to evaluate the ability of WHC to regulate the proliferation of breast cancer cells, using both time and concentration in treatment with WHC. In terms of ATP depletion, WHC induced more antiproliferation to three breast cancer cell lines, SKBR3, MCF7, and MDA-MB-231, than to normal breast M10 cell lines. SKBR3 and MCF7 cells showing higher sensitivity to WHC were used to explore the antiproliferation mechanism. Flow cytometric apoptosis analyses showed that subG1 phase and annexin V population were increased in breast cancer cells after WHC treatment. Western blotting showed that cleaved forms of the apoptotic proteins poly (ADP-ribose) polymerase (c-PARP) and cleaved caspase 3 (c-Cas 3) were increased in breast cancer cells. Flow cytometric oxidative stress analyses showed that WHC triggered reactive oxygen species (ROS) and mitochondrial superoxide (MitoSOX) production as well as glutathione depletion. In contrast, normal breast M10 cells showed lower levels of ROS and annexin V expression than breast cancer cells. Flow cytometric DNA damage analyses showed that WHC triggered γH2AX and 8-oxo-2′-deoxyguanosine (8-oxodG) expression in breast cancer cells. Moreover, N-acetylcysteine (NAC) pretreatment reverted oxidative stress-mediated ATP depletion, apoptosis, and DNA damage. Therefore, WHC kills breast cancer cells depending on oxidative stress-associated mechanisms.

Protamine-2 Deficiency Initiates a Reactive Oxygen Species (ROS)-Mediated Destruction Cascade during Epididymal Sperm Maturation in Mice.

Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Protamine-2 (Prm2)-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm’s antioxidant capacity, indicated by downregulation of key proteins like Superoxide dismutase type 1 (SOD1) and Peroxiredoxin 5 (PRDX5), ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.

Chronic exposure to environmentally relevant concentration of fluoride alters Ogg1 and Rad51 expressions in mice: Involvement of epigenetic regulation

Chronic exposure to fluoride (F) beyond the permissible limit (1.5 ppm) is known to cause detrimental health effects by induction of oxidative stress-mediated DNA damage overpowering the DNA repair machinery. In the present study, we assessed F induced oxidative stress through monitoring biochemical parameters and looked into the effect of chronic F exposure on two crucial DNA repair genes Ogg1 and Rad51 having important role against ROS induced DNA damages. To address this issue, we exposed Swiss albino mice to an environmentally relevant concentration of fluoride (15 ppm NaF) for 8 months. Results revealed histoarchitectural damages in liver, brain, kidney and spleen. Depletion of GSH, increase in lipid peroxidation and catalase activity in liver and brain confirmed the generation of oxidative stress. qRT-PCR result showed that expressions of Ogg1 and Rad51 were altered after F exposure in the affected organs. Promoter hypermethylation was associated with the downregulation of Rad51. F-induced DNA damage and the compromised DNA repair machinery triggered intrinsic pathway of apoptosis in liver and brain. The present study indicates the possible association of epigenetic regulation with F induced neurotoxicity.

Allium Cepa Remediates Oxidative Stress-Mediated Hepatic DNA Damage in Cadmium-Exposed Rats through Enhanced p53 Expression and Inhibition of Bcl2

BACKGROUND: Cadmium (Cd), a naturally occurring toxic metal, in addition to being cytotoxic, has been shown to be responsible for inducing free radical-dependent DNA damage in cells. Allium cepa is also known to ameliorate cadmium sulphate-induced organ toxicity through its antioxidant potential. The study was carried out to determine the ameliorative mechanisms of Allium cepa extract (ACE) in oxidative stress-mediated hepatic DNA damage in rats exposed to cadmium sulphate. MATERIALS AND METHODS: Twenty male adult wistar rats weighing 160-180g were used for this study. They were divided into four groups; group one (control), group two (Cd group), group three (Cd + ACE group) and group four (ACE group). Rats were administered 15 mg/kg CdSO4 and Allium cepa Extract (1 ml/100 g BW) for 28 days once per day (p.o.). Body weight changes (BWC), organ/body weight (OBW) ratio, feed conversion ratio (FCR), daily water intake (DWI) and daily feed intake (DFI) were monitored. Superoxide Dismutase (SOD), Catalase (CAT) activities and % DNA fragmentations were examined spectrophotometrically while immunohistochemical expression of Tumor Suppressor protein (p53) and cytoplasmic Bcl2 were also studied. Results were analyzed using SPSS 21 via Analysis of Variance (ANOVA). RESULTS AND DISCUSSION: Exposure to CD caused no significant change in BWC, OBW, FCR, DWI and DFI, but significantly decreased SOD and CAT activities. Significantly increase in % DNA fragmentation and Bcl2 expression and inhibited p53 expression were also observed in CD exposed rats. Decreased SOD and CAT activities, increased DNA fragmentation and Bcl2 expression together with inhibition of p53 expression orchestrated by cadmium exposure were ameliorated by Allium cepa treatments. CONCLUSION: Allium cepa remediates oxidative stress-mediated hepatic DNA damage by promoting P53 expression and inhibiting Bcl2 protein in rats exposed to cadmium sulphate.

MEASUREMENT OF DNA DAMAGE, OXIDATIVE STRESS, AND GENE EXPRESSION OF β-CATENIN AND P53 GENES IN LIVER AND BRAIN OF MALE MICE RECEIVING MONOSODIUM L-GLUTAMATE MONOHYDRATE

Introduction: Monosodium L-glutamate (MSG) monohydrate is a widespread nutritional additive and flavoring agent frequently consumed all over the world. In this study, we investigate the action of daily oral intake of MSG monohydrate in vivo using mammalian systems.
 Methods: Mice divided as follows: Group I (normal control), Group II, and Group III treated with MSG for 2 and 4 weeks, respectively. Brain and liver dissected out for the detection of fragmented DNA, DNA damage, and assay of oxidative stress markers. Moreover, expression levels of ß-Cat and p53 genes were measured by a real-time quantitative polymerase chain reaction.
 Results: The results showed a significant difference in MSG-treated group at the 2-time intervals than the control one regarding parameters of oxidative stress, and these were accompanied by a significant decline in glutathione (GSH) and a ratio of oxidized and reduced GSH in both tissues. Significant elevation of laddered DNA and oxidative DNA damage was observed in groups treated with MSG. In addition, a significant decline in gene expression of ß-Catenin in liver and brain tissues with elevations in the gene expression of p53 in the brain. Furthermore, the p53 gene in liver tissue was significantly upregulated in mice administered MSG for 15 days and was downregulated after 30 days of MSG intake compared with the control.
 Conclusion: According to our results, oral consumption of MSG leads to oxidative stress-mediated DNA damage and apoptosis.

Oxidative Stress-Induced DNA Damage and Apoptosis in Clove Buds-Treated MCF-7 Cells.

In recent decades, several spices have been studied for their potential in the prevention and treatment of cancer. It is documented that spices have antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. The main mechanisms of spices action included apoptosis induction, proliferation, migration and invasion of tumour inhibition, and sensitization of tumours to radiotherapy and chemotherapy. In this study, the ability of clove buds extract (CBE) to induce oxidative stress, DNA damage, and stress/survival/apoptotic pathways modulation were analysed in MCF-7 cells. We demonstrated that CBE treatment induced intrinsic caspase-dependent cell death associated with increased oxidative stress mediated by oxygen and nitrogen radicals. We showed also the CBE-mediated release of mitochondrial pro-apoptotic factors, signalling of oxidative stress-mediated DNA damage with modulation of cell antioxidant SOD (superoxide dismutase) system, and modulation activity of the Akt, p38 MAPK, JNK and Erk 1/2 pathways.

Poly-ubiquitinated p62/SQSTM1-mediated hemeoxygenase-1 stabilization plays a critical role in cadmium-induced apoptosis of mouse monocyte Raw264.7 cells

Cadmium (Cd) is a toxic heavy metal that can affect many organs, leading to serious pathological disorders through immune suppression. Here, we investigated the molecular mechanisms underlying the response of monocytes to Cd exposure. Cd treatment of Raw264.7 cells activated antioxidant enzymes, such as hemeoxygenase-1 (HO-1), superoxide dismutase, and catalase. Cd exposure upregulated p53, p53 phosphorylation, p21, and γH2AX phosphorylation. Cd exposure also induced poly ADP-ribose polymerase 1 (PARP-1) cleavage. These findings indicated that Cd induces apoptosis through oxidative stress-mediated DNA damage. Furthermore, upregulation of microtubule-associated protein 1 light chain 3B-II (LC3B-II), an indicator of autophagy, was found to depend on Cd concentration. Accumulation of an autophagy substrate p62/SQSTM1 in monomeric p62 and polyubiquitinated (polyUb)-p62 forms, was suppressed upon N-acetylcysteine treatment Cd-exposed Raw264.7 cells, indicating an impairment of autophagic degradation during oxidative stress. Knockdown of p62 in Raw264.7 cells using small interfering RNA (siRNA) downregulated HO-1 expression and reduced apoptosis. HO-1 knockdown suppressed apoptosis by decreasing the poly-ubiquitination of p62. Treatment with hemin and MG132 enhanced Cd-mediated increases in HO-1 and polyUb-p62 levels, resulting in increased apoptosis, which indicated that Cd-induced HO-1 accumulation is associated with polyUb-p62 formation. p62 and HO-1 interactions were demonstrated by immunofluorescence and immunoprecipitation assays. Additionally, p62 was downregulated in Raw264.7 cells in response to H2O2 and a low level of HO-1 was induced. Cells that were highly sensitive to Cd did not form polyUb-p62, resulting in insufficient HO-1 accumulation. These results suggest that maintenance of HO-1 stability via poly-ubiquitination of p62 in Cd-exposed monocytes promotes apoptosis, which could be involved in immune suppression.

Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene, which is frequently mutated in breast and ovarian cancers. BRCA1 plays a key role in the homologous recombination directed DNA repair, allowing its deficiency to act as a therapeutic target of DNA damaging agents. In this study, we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells. Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP), causing reactive oxygen species (ROS)-mediated DNA damage. This effect induced preferential apoptosis in BRCA1−/− breast cancer cells where DNA repair system is compromised. Two animal experiments and gene expression-associated patients’ survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC. Finally, the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET), another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage, showed a strong anticancer effect in BRCA1−/− breast cancer cells. Together, this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries, HDAC and BET.

Manoalide Preferentially Provides Antiproliferation of Oral Cancer Cells by Oxidative Stress-Mediated Apoptosis and DNA Damage.

Marine sponge-derived manoalide has a potent anti-inflammatory effect, but its potential application as an anti-cancer drug has not yet been extensively investigated. The purpose of this study is to evaluate the antiproliferative effects of manoalide on oral cancer cells. MTS assay at 24 h showed that manoalide inhibited the proliferation of six types of oral cancer cell lines (SCC9, HSC3, OC2, OECM-1, Ca9-22, and CAL 27) but did not affect the proliferation of normal oral cell line (human gingival fibroblasts (HGF-1)). Manoalide also inhibits the ATP production from 3D sphere formation of Ca9-22 and CAL 27 cells. Mechanically, manoalide induces subG1 accumulation in oral cancer cells. Manoalide also induces more annexin V expression in oral cancer Ca9-22 and CAL 27 cells than that of HGF-1 cells. Manoalide induces activation of caspase 3 (Cas 3), which is a hallmark of apoptosis in oral cancer cells, Ca9-22 and CAL 27. Inhibitors of Cas 8 and Cas 9 suppress manoalide-induced Cas 3 activation. Manoalide induces higher reactive oxygen species (ROS) productions in Ca9-22 and CAL 27 cells than in HGF-1 cells. This oxidative stress induction by manoalide is further supported by mitochondrial superoxide (MitoSOX) production and mitochondrial membrane potential (MitoMP) destruction in oral cancer cells. Subsequently, manoalide-induced oxidative stress leads to DNA damages, such as γH2AX and 8-oxo-2’-deoxyguanosine (8-oxodG), in oral cancer cells. Effects, such as enhanced antiproliferation, apoptosis, oxidative stress, and DNA damage, in manoalide-treated oral cancer cells were suppressed by inhibitors of oxidative stress or apoptosis, or both, such as N-acetylcysteine (NAC) and Z-VAD-FMK (Z-VAD). Moreover, mitochondria-targeted superoxide inhibitor MitoTEMPO suppresses manoalide-induced MitoSOX generation and γH2AX/8-oxodG DNA damages. This study validates the preferential antiproliferation effect of manoalide and explores the oxidative stress-dependent mechanisms in anti-oral cancer treatment.

Jingfukang induces anti-cancer activity through oxidative stress-mediated DNA damage in circulating human lung cancer cells

BackgroundMetastasis is the main cause of lung cancer death. As a seed of metastasis, circulating tumor cells are an important target for metastasis intervention. The traditional Chinese medicine, Jinfukang, has been clinically available for the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated the action and underlying mechanisms of Jinfukang against circulating lung tumor cells.MethodsThe cell counting kit-8 (CCK-8), colony formation and cell cycle assays were used to study the cell proliferation ability. Flow cytometry was used to detect the apoptosis and the expression level of ROS and Caspase-3. Comet and TUNEL assays were used to detect DNA damage. DNA damage related pathway protein was detected by western blot.ResultsJinfukang significantly inhibits the proliferation of CTC-TJH-01 cells by inducing G1 phase arrest and inhibits their colony formation in a dose-dependent manner. Moreover, Jinfukang induces apoptosis in CTC-TJH-01 cells through the ROS-mediated ATM/ATR-p53 pathway and DNA damage.ConclusionsOur findings suggest that Jinfukang may be a potential drug for lung cancer metastasis.

Aryl-phosphorus-containing flame retardants induce oxidative stress, the p53-dependent DNA damage response and mitochondrial impairment in A549 cells

Aryl phosphorus-containing flame retardants (aryl-PFRs) have been frequently detected with increasingly used worldwide as one of alternatives for brominated flame retardants. However, information on their adverse effects on human health and ecosystem is insufficient, with limited study on their molecular mode of action in vitro. In this study, the cytotoxicity, DNA damage, mitochondrial impairment and the involved molecular mechanisms of certain frequently detectable aryl-PFRs, including 2-ethylhexyldiphenyl phosphate (EHDPP), methyl diphenyl phosphate (MDPP), bisphenol-A bis (diphenyl phosphate) (BDP), isodecyl diphenyl phosphate (IDPP), cresyl diphenyl phosphate (CDP) and the structurally similar and widely used organophosphorus pesticide chlorpyrifos (CPF), were evaluated in A549 cells using high-content screening (HCS) system. Aryl-PFRs showed different lethal concentration 50 (LC50) values ranging from 97.94 to 546.85 μM in A549 cells using CCK-8 assay. EHDPP, IDPP, CDP, MDPP and CPF demonstrated an ability to induce DNA damage, evidenced by increased DNA content and S phase-reducing cell cycle arrest effect using fluorophore dye cocktail assay. Additionally, the selected aryl-PFRs induced mitochondrial impairment by the increasing mitochondrial mass and decreasing mitochondrial membrane potential. Moreover, BDP, MDPP, and CDP, which contain short alkyl chains showed their potential oxidative stress with intracellular ROS and mitochondrial superoxide overproduction from an initially relatively low concentration. Additionally, based on the promotion of firefly luminescence in p53-transfected A549 cells, p53 activation was found to be involved in aryl-PFRs-induced DNA damage. Further real-time PCR results showed that all selected aryl-PFRs triggered p53/p21/gadd45β-, and p53/p21/mdm2-mediated cell cycle pathways, and the p53/bax mediated apoptosis pathway to induce DNA damage and cytotoxic effects. These results suggest that aryl-PFRs (e.g., BDP, MDPP, CDP) cause oxidative stress-mediated DNA damage and mitochondrial impairment, and p53-dependent pathway was involved in the aryl-PFRs-induced DNA damage and cell cycle arrest. In conclusion, this study improves the understanding of PFRs-induced adverse outcomes and the involved molecular mechanism.

C-Myc activation promotes cofilin-mediated F-actin cytoskeleton remodeling and telomere homeostasis as a response to oxidant-based DNA damage in medulloblastoma cells

Medulloblastoma (MB) is a common and highly aggressive pediatric brain tumor of a heterogeneous nature. According to transcriptome-based profiling, four molecular subgroups of MB have been revealed, namely WNT, SHH, Group 3 and Group 4. High MYC mRNA expression and MYC gene amplification in MB have been considered as indicators of poor prognosis. However, the role of c-Myc in MB biology is still not well established. In the present study, the effects of c-Myc activation in UW228-MycER MB cell line were investigated using 4-hydroxytamoxifen (4-OHT) induction system. Upon 4-OHT stimulation, an increase in metabolic activity, large-cell/anaplastic (LC/A) phenotype and oxidative stress-mediated DNA damage were observed. However, 53BP1 foci were not implicated in DNA damage response. Instead, cofilin nuclear translocation, changes in F-actin cytoskeleton and the levels of cytoskeletal proteins were shown. Moreover, the telomere length was found to be unaffected that may be associated with the upregulation of TRF proteins. Transcription of nascent RNA (synthesis of new rRNA) and the expression of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA were also elevated. Moreover, increased levels of DNMT2, a modulator of stress responses, were observed. A small fraction of cells responded differently as oncogene-induced senescence was also noticed. We postulate that c-Myc-mediated modulation of genetic stability of MB cells may trigger cellular heterogeneity and affect adaptive responses to changing environment.

In vitro genotoxicity assessment of nickel(II) oxide nanoparticles on lymphocytes of human peripheral blood.

The current study was intended to elucidate the cytotoxicity, genotoxicity ability of nickel oxide (NiO) nanoparticles (NPs) and assessment of preliminary mechanism of the toxicity. Characterization studies showed that NiO-NPs have a particle size of 17.94 (±3.48) nm. The particle size of the NPs obtained by dynamic light scattering method in Milli-Q and RPMI 1640 media was 189.9 (±17.1) and 285.9 (±19.6) nm, respectively. The IC50 concentration for NiO-NPs after 24hours of treatment was estimated as 23.58μg/mL. Comet and cytokinesis-block micronucleus assays revealed a significant dose- and time-dependent genotoxic potential of NiO-NPs. Morphological assessment of the lymphocytes upon exposure to NiO-NPs showed that the mechanism of toxicity was apoptosis. Reactive oxygen species analysis and lipid peroxidation patterns were aligned with the cytotoxicity and genotoxicity endpoints. Thus, the preliminary mechanism of NiO-NPs for cytotoxicity on lymphocytes was assumed to be oxidative stress-mediated apoptosis and DNA damage. Furthermore, these NiO-NPs are considered a potentially hazardous substance at environmentally significant levels. Further investigations are suggested to understand the immunotoxic effects of NiO-NPs.

TiO2 nanoparticles induced oxidative stress mediated DNA damage in the liver of adult male Wistar rats

TiO2 nanoparticles induced oxidative stress mediated DNA damage in the liver of adult male Wistar rats

Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma.

Hepatitis B virus (HBV) infection is a global health problem that causes a wide range of pathological outcomes, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic inflammation via enhanced inflammation, oxidative stress-mediated DNA damage, and hepatocyte proliferation. In the natural course of HBV infection, the accumulation of naturally occurring mutations in the HBV genome can generate several mutant types of HBV-encoded proteins, including three different proteins in the S ORF (SHBs, MHBs, and LHBs) and HBcAg in the C ORF, which could contribute to enhanced ER stress in infected hepatocytes mainly via increased ER accumulation of mutant proteins. However, it seems that there may be distinct capacity and pathway in ER stress-induction and distinct resulting clinical outcomes between HBV variants. In addition, the role of HBxAg mutations in ER stress remains unknown. However, it has been reported that HBxAg itself could exert ER stress in infected cells, resulting in HCC generation in chronic HBV patients. To date, review papers regarding ER stress-mediated HBV mutation have been limited into a specific mutation type: preS2 deletion. So, in this review, we will discuss details about various mutation types in all four regions of the HBV genome (preS1, preS2, S, and C) related to ER stress and their distinct ER stress mechanisms and clinical outcomes in terms of mutation types.

Adaptation to chronic exposure to sepantronium bromide (YM155), a prototypical survivin suppressant is due to persistent DNA damage-response in breast cancer cells.

Sepantronium bromide (YM155), originally developed against the anti-apoptotic protein survivin, performed exceptionally well in pre-clinical and phase I clinical trials. However, in phase II trials of several cancer types including breast cancer it performed poorly. Additionally, no definitive correlation between survivin level and response to therapy was found. In an attempt to understand the true reason of the late-stage failure of this promising drug, we developed YM155-resistant MCF-7 breast cancer cell line and characterized side-by-side with the drug-naïve parental cell line. Chronic YM155 treatment resulted in downregulation of survivin expression yet triggered cellular responses typical of adaptation to persistent DNA damage. Lowering endogenous antioxidant glutathione level and activity of cell cycle check-point kinase restored YM155 activity. Thus, contrary to its development as a survivin suppressant, YM155 primarily acts as a chemotherapeutic drug causing oxidative stress-mediated DNA damage. Adaptation to long-term exposure to YM155 can be prevented and/or overcome by interfering with detoxification and DNA damage-response pathways. Finally, proteins associated with DNA damage-response pathway will be more appropriate as predictive biomarkers of YM155 in breast tumor cells.

Oxidative stress-modulating drugs have preferential anticancer effects - involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration.

To achieve preferential effects against cancer cells but less damage to normal cells is one of the main challenges of cancer research. In this review, we explore the roles and relationships of oxidative stress-mediated apoptosis, DNA damage, ER stress, autophagy, metabolism, and migration of ROS-modulating anticancer drugs. Understanding preferential anticancer effects in more detail will improve chemotherapeutic approaches that are based on ROS-modulating drugs in cancer treatments.