Genetic Association between ERCC5 rs17655 Polymorphism and Colorectal Cancer Risk: Evidence Based on a Meta-analysis

Background: Previous studies evaluating the association between the excision repair cross complementinggroup 5 (ERCC5) gene rs17655 polymorphism and colorectal cancer susceptibility generated controversial results.To generate large-scale evidence on whether the ERCC5 rs17655 polymorphism might indeed be associatedwith colorectal cancer susceptibility, the present meta-analysis was performed. Materials and Methods: Datawere collected from PubMed, Embase and Web of Science, with the last report up to Apr 03, 2015. Odds ratios(ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association. Results: A total ofnine studies including 5,102 cases and 6,326 controls based on the search criteria were included and significantassociations were found between ERCC5 rs17655 polymorphism CG vs GG overall (OR = 1.29, 95% CI=1.18~1.40) and in the dominant model (OR=1.23, 95% CI =1.13~1.33). On subgroup analysis by ethnicity andsource of controls, the ERCC5 rs17655 polymorphism was found to correlate with the pathogenesis of colorectalcancer among Asians and Caucasians and with hospital-based populations. Conclusions: This meta-analysissuggests that the ERCC5 rs17655 polymorphism might contribute to genetic susceptibility to colorectal cancer.     

Concentration- Dependent Effects of Curcumin on 5-Fluorouracil Efficacy in Bladder Cancer Cells

Purpose: Curcumin (Cur), a herbal ingredient with anticancer properties, has been shown to inhibit growth of malignant cells in vivo and in vitro. However, studies on combination therapy of Cur with chemotherapeutic drugs have been limited. Here, effects of Cur on the cytotoxicity of 5-Fluorouracil (FU) were investigated with epithelial bladder cancer cells (EJ138) in vitro. Methods: EJ138 cells were treated with 5 and 15 μM of Cur and/ or 100 μM of FU. Cell viability was measured by sulforhodamine B colorimetric assay. The glucose concentration as an index of cell metabolism was evaluated by an enzymatic method. Total oxidant and antioxidant capacities were estimated by the ferrous oxidation-xylenol (FOX1) method and ferric reducing antioxidant power assay (FRAP), respectively. Results: Combination of 5 μM Cur with FU significantly reduced its cytotoxicity in EJ138 cells, while 15 μM Cur caused an opposite increase. Significant increase in glucose concentration at 24 h and decrease in the FRAP value at 48 h incubation was observed in cells treated with FU in combination with Cur. There were no significant changes in total oxidant capacity with the combination therapy. Conclusion: Our findings suggest a crucial role of Cur concentration in regulating chemotherapeutic agent-induced cytotoxicity. Further investigations are needed to understand the precise mechanisms of action of Cur and determine appropriate doses with combination therapy for clinical application against human cancers.     

Overweight,Obesity, Oxidative Stress and the Risk of Breast Cancer

There is growing scientific evidence linking excess body weight to breast cancer risk. However, there is nocommon consensus on this relation due partly to methodologies used, populations studied and the cancer subtype.We report here a summary of the present state of knowledge on the role of overweight and obesity in pathogenesisof breast cancer and possible mechanisms through which excess body weight might influence the risk, focusingon the role of oxidative stress in breast cancer etiology. The findings demonstrate duality of excess body weightaction in dependence on menopausal status: a statistically significant increased risk in postmenopausal overweight/obese women and non-significant preventive effect among premenopausal women. Due to several gaps in theliterature on this topic, additional studies are needed. Future research should address factors influencing theexcess body weight - breast cancer relationship, such as race/ethnicity, tumor subtype, receptor status, the mostappropriate measure of adiposity, reproductive characteristics, and lifestyle components.     

Roles of Oxidative Stress in the Development and Progression of Breast Cancer

Oxidative stress is caused by an imbalance in the redox status of the body. In such a state, increase of freeradicals in the body can lead to tissue damage. One of the most important species of free radicals is reactiveoxygen species (ROS) produced by various metabolic pathways, including aerobic metabolism in the mitochondrialrespiratory chain. It plays a critical role in the initiation and progression of various types of cancers. ROS affectsdifferent signaling pathways, including growth factors and mitogenic pathways, and controls many cellularprocesses, including cell proliferation, and thus stimulates the uncontrolled growth of cells which encourages thedevelopment of tumors and begins the process of carcinogenesis. Increased oxidative stress caused by reactivespecies can reduce the body’s antioxidant defense against angiogenesis and metastasis in cancer cells. Theseprocesses are main factors in the development of cancer. Bimolecular reactions cause free radicals in whichcreate such compounds as malondialdehyde (MDA) and hydroxyguanosine. These substances can be used asindicators of cancer. In this review, free radicals as oxidizing agents, antioxidants as the immune system, andthe role of oxidative stress in cancer, particularly breast cancer, have been investigated in the hope that betteridentification of the factors involved in the occurrence and spread of cancer will improve the identification oftreatment goals.     

姜黄素对DMBA诱发的地鼠口腔癌预防作用

背景与目的:选用二甲基苯并蒽(7,12-dimethylbenz(a)anthracene,DMBA)诱发的金黄色地鼠口腔癌模型,进行了姜黄素对口腔癌的预防作用研究,并探讨其防癌机制。材料与方法:试验设阳性对照组(局部涂0.5%DMBA,每周3次,共14周)、二个姜黄素组(在涂DMBA2周前开始分别涂5μmol/L和10μmol/L姜黄素至14周实验结束)和阴性对照组(仅涂石蜡油)。结果:10μmol/L姜黄素处理显著降低了口腔肿瘤发病率和癌发病率,5μmol/L对肉眼肿瘤数目和体积、异常增生及癌数目的抑制分别降低了33.8%、36.3%、37.6%和29.0%。10μmol/L分别降低了46.0%、63.7%、44.7%和37.0%。此外,姜黄素处理均抑制了单纯增生和异常增生组织的微核形成和单纯增生、异常增生和癌组织的Brdu增殖指数。结论:姜黄素对DMBA诱发的地鼠口腔癌有预防作用,其机制与保护DNA损伤、抑制细胞增殖有关。     

Association between ERCC1 Polymorphism and the Risk and Clinicopathological Features of Breast Cancer in Thai Women in the Lower Northeastern Region

Background: Breast cancer is a major public health problem around the world, including Thailand and it has the highest ranking among female cancer. Currently, the diversity or polymorphism of ERCC1 gene (excision repair cross-complementary group 1 gene or ERCC1) was reported to associate with an increased risk of breast cancer. This study aims to investigate the relationship between ERCC1 polymorphism and the breast cancer risk in the lower northeastern region women of Thailand. Materials and Methods: One hundred fifty one samples from breast cancer patients and 120 samples from healthy control group were analysed. Genomic DNA was extracted from white blood cell of all samples. The real-time polymerase chain reaction (qPCR) was used to demonstrate genetic polymorphism of ERCC1. Results: The results showed that the ERCC1 rs11615 polymorphism variant AG was associated with an increased risk of breast cancer. This study demonstrated that the frequency of ERCC1 rs11615 in patients with breast cancer was higher than healthy control group. The ERCC1 polymorphism variant AG carrier presented 3.53-folds high risk of breast cancer [odds ratio (OR) = 3.53, 95% CI = 1.61-7.74, P = 0.001]. In addition, when age, menopause period, number of child, smoking and alcohol drinking were adjusted, the ERCC1 rs11615 variant AG carrier was associated with increased breast cancer risk to 3.97 folds, with OR = 3.79, 95% CI = 1.62-8.84, P = 0.002. Conclusions: This study showed that ERCC1 rs11615 genotype AG was associated with breast cancer risk in the lower northeastern region women of Thailand.     

ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma

BACKGROUND:

The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS).

METHODS:

The authors analyzed excision repair cross‐complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG) (NER), excision repair cross‐complementation group 1 (ERCC1) (NER), and breast cancer 1 (BRCA1) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate‐use program. The 6‐month progression‐free rate (PFR), progression‐free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1, and BRCA1 status using log‐rank tests.

RESULTS:

High expression of the common allele (aspartic acid at codon 1104) of ERCC5, high expression of ERCC1, and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine‐to‐cytosine (T→C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple‐adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS.

CONCLUSIONS:

In the current study, ERCC5, ERCC1, and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS. Cancer 2011. © 2011 American Cancer Society.     

Effect of the ERCC1 (C118T) Polymorphism on Treatment Response in Advanced Non-Small Cell Lung Cancer Patients Undergoing Platinum-Based Chemotherapy

For advanced non-small-cell lung cancer (NSCLC) cases, a platinum-based regimen is the first-line chemotherapy treatment. The excision repair cross-complementing group 1 (ERCC1) plays an important role in DNA repair and has been related to resistance to platinum chemotherapy. This study aimed to investigate the effects of the ERCC1 (C118T) polymorphism on treatment response in 26 Thai advanced NSCLC patients receiving first line platinum-based chemotherapy during January to July 2015 at King Chulalongkorn Memorial Hospital (KCMH). DNA was extracted from peripheral blood lymphocytes and the single nucleotide polymorphism of ERCC1 was genotyped using a real-time PCR method with the TaqMan assay. The distribution of C/C, C/T and T/T genotypes was 57.7 %, 34.6 % and 7.7 %, respectively. The response rate to platinum-based chemotherapy in the wild type (C/C) of ERCC1 (C118T) was better than with the variant types (C/T and T/T) but the difference was not statistically significant (29.7% vs 9.1%, P=0.274). The results showed that a genetic polymorphism in ERCC1 might influence patient response to platinum-based chemotherapy. Further multicenter studies are now required to confirm the results of our study.     

Oxidative Stress and Skin Diseases: Possible Role of Physical Activity

Background: The skin is the largest body organ that regulates excretion of metabolic waste products,temperature, and plays an important role in body protection against environmental physical and chemical,as well as biological factors. These include agents that may act as oxidants or catalysts of reactions producingreactive oxygen species (ROS), reactive nitrogen species (RNS), and other oxidants in skin cells. An increasedamount of the oxidants, exceeding the antioxidant defense system capacity is called oxidative stress, leading tochronic inflammation, which, in turn, can cause collagen fragmentation and disorganization of collagen fibersand skin cell functions, and thus contribute to skin diseases including cancer. Moreover, research suggests thatoxidative stress participates in all stages of carcinogenesis. We report here a summary of the present state ofknowledge on the role of oxidative stress in pathogenesis of dermatologic diseases, defensive systems againstROS/RNS, and discuss how physical activity may modulate skin diseases through effects on oxidative stress.The data show duality of physical activity actions: regular moderate activity protects against ROS/RNS damage,and endurance exercise with a lack of training mediates oxidative stress. These findings indicate that the redoxbalance should be considered in the development of new antioxidant strategies linked to the prevention andtherapy of skin diseases.     

Change in Adiponectin and Oxidative Stress after Modifiable Lifestyle Interventions in Breast Cancer Cases

Background: Breast cancer is one of the most frequent diseases in women today. Little information exists onmodifiable lifestyle factors including effects of ginger supplements (as an anti-oxidant and anti-inflammatoryherbal) and water-based exercise on biomarkers related to oxidative stress such as malondialdehyde (MDA),nitric oxide (NO) and glutathione peroxidase (GPx) and adiponectin in obese women with breast cancer. Theaim of this study was to determine the single and concomitant effect of 6-wks water-based exercise and oralginger supplement on the aforesaid markers in obese women with breast cancer. Materials and Methods: Fortywomen diagnosed with breast cancer (48±5.4 years, 76±9 kg, fat mass 41.8±4%), volunteered to participate in thestudy. Subjects were randomly assigned into four groups; placebo, water-based exercise, ginger supplement andwater-based exercise+ginger supplement groups. Subjects in the ginger supplement group and the water-basedexercise+ginger supplement group orally received 4 capsules (each capsule contained 750 mg), 7 days a week for 6weeks. The water-based exercise program featured progressive increase in intensity and time, ranging from 50%to 75% of heart rate reserve, in a pool with 15 meters width, 4 times a week for 6 weeks. Fasting blood sampleswere collected at pre-test and post-test time points. Results: The ginger supplementation and or the water-baseexercise resulted in an increase of adiponectin, NO and GPx and reduction MDA, as compared to pre-test values.However, the combined intervention (water-base exercise and ginger supplement) group showed significantly afar better effect on the biomarkers related to oxidative stress and adiponectin levels, as compared to the waterbaseexercise or ginger supplement alone groups and the age-matched placebo group. Conclusions: Our resultsrevealed that water-base exercise is a non-drug therapeutic strategy to reduce systemic stress in obese womensuffering from breast cancer. Further, ginger supplementation alone or in combination with training, also playan important role in the pathogenesis of oxidative stress in obese women diagnosed with breast cancer.     

ERCC1和XRCC3基因多态性在接受含铂方案化疗NSCLC中的疗效预测作用

[目的]探讨DNA修复基因ERCC1 118和XRCC3 241多态性对于接受一线含铂化疗方案的非小细胞肺癌（NSCLC）患者的疗效预测作用。[方法]130例晚期接受含铂化疗的NSCLC患者进入研究．应用Taqman探针结合实时荧光PCR方法分析其外周血基因多态性．分析ERCC1 118和XRCC3 241多态性与疗效、疾病进展时间和总体生存期之间的关系。[结果]130例患者的总体有效率为20％．中位生存时间为15个月．ERCC1 118和XRCC3 241多态性与疗效无显著相关性。ERCC1 118基因型C/T或T/T患者的生存时间显著延长（P=0.003）。Cox多因素分析显示,ERCC1 118基因型C/T或T/T以及化疗有效患者的生存期显著延长。[结论]DNA修复基因ERCC1 118基因型C／T或T/T多态性可以延长NSCLC患者铂类治疗后的生存时间．     

ERCC1与XPD基因多态性对NSCLC化疗敏感性影响的研究进展

临床III-IV期NSCLC占肺癌的大多数,以铂类药物为基础联合第三代新药是晚期NSCLC的一线化疗方案,近年来多项研究表明,个体间化疗敏感性的不同可能与基因修复能力有关,本文主要对核苷酸切除修复系统的关键基因ERCC1、XPD的多态性与铂类药物化疗敏感性关系的最新研究成果做简要综述。     

Status of Oxidative Stress and Antioxidant Levels in Smokers with Breast Cancer from Western Nepal

Background: Research indicates that oxidative stress induced by smoking plays a role in breast cancer. Inview of these reports, we aimed to study th relationship between smoking and oxidative stress in breast cancerpatients from the western region of Nepal. Materials and Methods: The study included a control group of 42females (non-smoking healthy women) and a test group sudivided into Group I consisting of 46 female breastcancer patients who were smokers and Group II consisting of 42 non-smoking breast cancer patients. Detailedhistory of the patients was collected with the help of pre-test proforma. Plasma levels of malondialdehyde (MDA),total antioxidant activity (TAA) which represents total dietary antioxidants, vitamin C and α- tocopherol wereestimated by standard methods. Statistical analysis was done using SPSS version 16. Results: The plasma MDA,TAA, vitamin C and α- tocopherol were 1±1.4nmol/ml, 918±207μmol/L, 1±0.24mg/dL and 0.94±0.31mg/dL incontrols, 5±1.2nmol/ml, 458±166 μmol/L, 0.64±0.32mg/dL and 0.5±0.3mg/dL in Group-I and 2.56±1.2nmol/ml,663±178 μmol/L, 0.78±0.2mg/dL and 0.77±0.2mg/dL in Group- II, respectively. Vitamin C, α- tocopherol andTAA (p=0.001) were significantly reduced whereas MDA (p=0.001) was significantly raised in Group-I whencompared to controls and Group-II. Conclusions: We observed a significant rise in oxidative stress and lowlevels of antioxidants in breast cancer patients with smoking habit. It is well known that free radicals facilitatethe progression of breast cancer, possibly increasing the risk of progression to the next stage.     

Impact of Breast Cancer and Combination Chemotherapy on Oxidative Stress,Hepatic and Cardiac Markers

Purpose

Carcinoma of the breast is the most prevalent cancer among Egyptian women and constitutes 29% of National Cancer Institute cases. The aim of this study was to determine the effect of breast cancer on oxidative stress, cardiac markers and liver function tests, moreover the role of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in the treatment of breast cancer and its mechanism through changing the measured markers.

Methods

Forty female breast cancer patients who were admitted to the Department of Oncology of the Beni-Suef University Hospital were enrolled in the study. This study included three arms: a control group of healthy age-matched females (n=20), breast cancer patients who weren''t receiving treatment (n=20), and patients undergoing treatment with anticancer combination drugs FAC (n=20). Blood samples collected from the control subjects and patients were analysed to determine levels of catalase, reduced glutathione (GSH), uric acid, nitric oxide (NO), malondialdehyde, creatine kinase (CK), lactate dehydrogenase (LDH), liver enzymes (alanine aminotransferase and aspartate aminotransferase), and creatinine.

Results

The levels of catalase and GSH were significantly reduced (p<0.05) in breast carcinoma and FAC treated breast cancer patients. The lipid peroxidation and NO levels were significantly enhanced in both untreated and FAC treated breast cancer patients. The CK and LDH were significantly enhanced (p<0.05) in the FAC group.

Conclusion

The results from the present study show that oxidative stress is implicated in breast carcinoma and chemotherapy aggravates this oxidative stress which causes damage to many cellular targets and has the main side effect of cardiotoxicity.     

ERCC1 C19007T polymorphism and the risk and invasiveness of cervical cancer in Korean women

Aim: Various DNA alterations by environmental or endogenous carcinogens, if not repaired, can cause genetic mutagenesis, resulting in carcinogenesis. A polymorphic variant of excision repair cross‐complementation group 1 (ERCC1) (the DNA repair gene) may be associated with carcinogenesis due to reduced DNA repair capacity. The aim of this study was to investigate whether the ERCC1 C19007T polymorphism might be associated with the increased risk and invasiveness of cervical cancer in Korean women. Methods: Peripheral blood samples from 229 patients with invasive cervical cancer and 204 non‐cancer controls were used to detect the ERCC1 C19007T polymorphism by performing a polymerase chain reaction restriction fragment length polymorphism assay. Allelic frequencies and genotype distributions in the patients’ group were compared with those in the control group. The relationship between this polymorphism and cancer invasiveness was also evaluated by analyzing clinicopathological parameters including International Federation of Gynecology and Obstetrics stage, lymph node status, histological type and parametrial invasion. The analytic methods used were the χ² test and logistic regression analysis. Results: The allelic frequencies of patients (A, 0.758; C, 0.242) were not significantly different from that of controls (A, 0.755; C, 0.245) (P = 0.925). The C/C genotype had no increased risk for cervical cancer susceptibility compared with the TT genotype (P = 0.932). A subgroup analysis of the clinicopathological parameters in the cancer group also showed that there is no significant association between the ERCC1 C19007T polymorphism and cervical cancer invasiveness. Conclusion: This study shows that the ERCC1 C19007T polymorphism might not be associated with the risk and invasiveness of cervical cancer in Korean women.     

Association between Polymorphisms of ERCC5 Gene and Susceptibility to Gastric Cancer: A Systematic Review and Meta-Analysis

Background: several epidemiological studies have suggested that polymorphisms of the Excision Repair Cross Complementing Group-5 (ERCC5) gene might be related to gastric cancer risk; however, the results have been inconsistent or controversial. Therefore, we have performed a systematic review and meta-analysis to clarify the association between the ERCC5 gene polymorphisms and gastric cancer risk. Materials and Methods: An electronic search was conducted of several databases, including PubMed, Web of Science, and Google Scholar for articles that describe the association between polymorphisms of the ERCC5 gene and susceptibility of gastric cancer. Results: A total of 33 case control studies in 15 publications were included in the present meta-analysis. There were significant associations between gastric cancer susceptibility and ERCC5 gene rs751402 C>T (T vs. C: OR = 1.166, 95% C = 1.066-1.274, p= 0.001; TT vs. CC: OR = 0.723, 95% CI = 0.587-0.890, p = 0.002; TT+TC vs. CC: OR = 0.853, 95% CI = 0.757-0.961, p = 0.009; TT vs. TC+CC: OR = 0.793, 95% CI = 0.659-0.955, p = 0.015), rs2296147 T>C (C vs. T: OR = 1.268, 95% C = 1.049-1.532, p= 0.014), rs873601 G>A polymorphisms (A vs. G, OR = 1.087, 95% C = 1.021-1.159, p= 0.010; AA vs. GG, OR = 1.184, 95% CI = 1.043-1.343, p = 0.009, AA vs. AG+GG, OR = 1.156, 95% CI = 1.040-1.284, p = 0.007), but not rs2094258 C>T and rs1047768 T>C. Conclusion: the current meta-analysis demonstrates that rs751402 C>T, rs2296147 T>C, and rs873601 G>A polymorphisms of ERCC5 gene are associated with the susceptibility of gastric cancer.     

Interactions between Oxidative Stress,Lipid Profile and Antioxidants in Breast Cancer: A Case Control Study

Oxidant/antioxidant balance has been suggested as an important factor for initiation and progression of cancer.The objective of this study was to determine changes in the levels of malondialdehyde (MDA), nitric oxide (NO),total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, total antioxidant capacity (TAC), glutathioneperoxidase (GSH-Px), and superoxide dismutase (SOD) activities in serum samples of breast cancer patients(n=30) and healthy subjects (n=100). MDA and NO levels were found to be increased in breast cancer patientscompared to the healthy subject group (p<0.05). Total cholesterol and triglycerides were elevated; and HDLcholesterollevel was found to be decreased in the cancer patients as compared to the healthy subjects (p<0.05).Compared to the healthy group, both serum TAC levels (p<0.001) and activity of SOD and GSH-Px (p=0.05) werefound to be decreased in the breast cancer patients as compared to the healthy controls. Considering the datapresented in this study, we suggest that free radicals induce lipid eroxidation and peroxidation of unsaturatedfatty acid with decreased activity of enzymatic antioxidants in breast cancer.     

Chemoprevention by Butea Monosperma of Hepatic Carcinogenesis and Oxidative Damage in Male Wistar Rats

In this communication, we document chemopreventive effects of Butea monosperma extract on hepatic ‍carcinogenesis and on tumor promoter induced markers and oxidative stress in male Wistar rats. Treatment of male ‍Wistar rats for five consecutive days with 2-AAF i.p. induced significant hepatic toxicity, oxidative stress and ‍hyperproliferation. Pretreatment of B.monosperma extract (100 and 200 mg/kg body weight) prevented oxidative ‍stress by restoring the levels of antioxidant enzymes and also prevented toxicity at both doses. The promotion ‍parameters induced (ornithine decarboxylase activity and DNA synthesis) by 2-AAF administration in diet with ‍partial hepatectomy (PH) were also significantly suppressed dose dependently by B. monosperma. Thereafter, we ‍proceeded with studies on rat liver carcinogenesis. After fourteen days of DEN treatment, dietary administration of ‍2-AAF with PH resulted in a 100% incidence of tumors in the animals. However, B.monosperma caused reduction in ‍the number of tumors/ rat and percentage of tumor bearing rats at the end of the study, as confirmed histologically. ‍Thus, our data suggest that B.monosperma extract is a potent chemopreventive agent which suppresses 2-AAFinduced ‍hepatic carcinogenesis and oxidative damage in Wistar rats. The protective activity of the plant might be ‍due to the two major constituents (butrin and isobutrin).