Lipid peroxidation, free radical production and antioxidant status in breast cancer

Reactive oxygen metabolites (ROMs), including superoxide anion (O₂ ^·–), hydrogen peroxide (H₂O₂) and hydroxyl radical (^·OH), play an important role in carcinogenesis. There are some primary antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) which protect against cellular and molecular damage caused by the ROMs. We conducted the present study to determine the rate of O₂ ^·– and H₂O₂ production, and concentration of malondialdehyde (MDA), as an index of lipid peroxidation, along with the SOD, GPx and CAT activities in 54 breast cancer (BC) patients. Forty-two age- and sex-matched patients with minor surgical problems, who had no history of any neoplastic or breast disorders, were taken as controls.The rate of O₂ ^·– production was significantly higher (p<0.001) in BC patients than controls, irrespective of clinical stages and menopausal status. Similarly, H₂O₂ production was significantly higher in BC patients, especially in stage III and postmenopausal groups, as compared to the respective controls. MDA concentration was also observed significantly elevated in stage II (p<0.001), stage III (p<0.01), postmenopausal (p<0.005), and premenopausal (p<0.02) group as compared to their corresponding controls. SOD and GPx activities were found significantly raised in all the groups (p<0.001), except the GPx activity was found a smaller alteration in stage IV (p<0.02). On the contrary, CAT activity was found significantly depressed in all the study groups. The maximum depression was observed in stage II (–61.8%). Lower CAT activity in our study may be the effect of higher production of ROMs, particularly O₂ ^·– and ^·OH. SOD and GPx, however, were less effected by these higher ROMs production. The results of our study have shown a higher ROMs production and decreased CAT activity, which support the oxidative stress hypothesis in carcinogenesis. The relatively higher SOD and GPx may be due to the response of increased ROMs production in the blood. However, the higher SOD and GPx activities may be inadequate to detoxify high levels of H₂O₂ into H₂O leading to the formation of the most dangerous ^·OH radical followed by MDA. Therefore, administration of CAT may be helpful in the management of BC patients. However, further elaborate clinical studies are required to evaluate the role of such antioxidant enzymes in BC management.     

锰超氧化物歧化酶在肿瘤发生发展过程中的研究进展

活性氧与肿瘤的发生发展有着密切关系。锰超氧化物歧化酶(MnSOD)作为清除线粒体基质中超氧阴离子的抗氧化酶, 对维持线粒体的氧化还原稳态、保护线粒体DNA具有极为重要的作用。研究发现MnSOD在不同肿瘤中的表达水平不一, 同时具有抑癌和促癌双面功能, 但其功能转换机制仍不明晰。本文拟探讨MnSOD在肿瘤发生发展中的作用, 并对其表达水平和活性的主要调控机制进行综述。     

Cu/Zn superoxide dismutase plays a role in angiogenesis.

Endothelial cells produce oxygen radicals spontaneously and this process is augmented by hypoxia/reoxygenation. Cu/Zn superoxide dismutase (SOD-1) is an important enzyme in cellular oxygen metabolism. To determine whether alterations in SOD-1 activity affect angiogenesis we used transgenic SOD-1 (Tg-SOD) mice with elevated level of SOD-1. Angiogenesis induced subcutaneously by bFGF in Tg-SOD mice was 3-fold higher than in control non-transgenic (ntg) mice. Oral administration of disulfiram (DSF), an inhibitor of SOD-1, inhibited angiogenesis in Tg-SOD mice as well as in CD1 nude mice. Effects of DSF on cultured cells were also tested. Application of DSF to cultured bovine capillary endothelial (BCE) cells caused inhibition of DNA synthesis and induction of apoptosis. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. DSF also reduced the level of glutathione and the production of H(2)O(2) in BCE cells. Moreover, PC12-SOD cells with elevated SOD-1 were less sensitive to DSF treatment then control cells. These data indicate that the effects of DSF are mediated by inhibition of SOD-1 activity. Tumor development is known to largely depend on angiogenesis. We found that oral administration of DSF to mice caused significant inhibition of C6 glioma tumor development and marked reduction (by 10-19-fold) in metastatic growth of Lewis lung carcinoma. The data suggest a role for SOD-1 in angiogenesis, establish DSF as a potential inhibitor of angiogenesis and raise the possibility that attenuating SOD-1 activity may be important in treatment of angiogenesis-dependent pathologies.     

Soy isoflavone supplementation elevates erythrocyte superoxide dismutase,but not plasma ceruloplasmin in postmenopausal breast cancer survivors

Summary Soy isoflavone antioxidant effects may help prevent breast cancer re-occurrence, but isoflavone estrogen-like actions may increase breast cancer risk. These isoflavone actions can be reflected by effects on two copper enzymes activities, superoxide dismutase 1 (SOD 1), which has antioxidant function relevant to breast cancer prevention, and ceruloplasmin, which has its synthesis up-regulated by estrogen, and for which high values are associated with high breast cancer risk. A soy isoflavone-rich concentrate supplement was examined for effects on these two copper enzyme activities in post-menopausal breast cancer survivors (n = 7) in a crossover design with a placebo (24 days on supplement or placebo; 14 day wash out). The soy concentrate, but not the placebo, increased erythrocyte SOD 1 activities, but not ceruloplasmin activities or protein. The effect on superoxide dismutase activities was not likely due to increased copper intake since analysis of the soy extract showed little copper. The effect on superoxide dismutase was not accompanied by a change in urinary contents of 8-deoxyhydroxyguanosine, a DNA oxidant product, though perhaps this would change with a longer intervention. In summary, in regard to two copper enzyme activities, an isoflavone-rich soy concentrate showed an antioxidant effect considered relevant to breast cancer, but not an effect associated with estrogenic activity and increased breast cancer risk.     

恶性淋巴瘤超氧化物歧化酶活力的改变及临床意义

用邻苯三酚自氧化法测定了５０例恶性淋巴瘤（ＭＬ）不同病期（初发期、级解期、复发期）、不同病理类型（ＮＨＬ及ＨＤ）、不同临床分期（Ｉ、Ⅱ、Ⅲ、Ⅳ期）病人的红细胞及血浆超氧化物歧化酶＊力变化。结果表明ＭＬ初发及复发病例的红细胞ＳＯＤ活力明显降低，血浆ＳＯＤ活力明显升高（Ｐ均＜０．０１）。缓解期病人红细胞及血浆ＳＯＤ活力大致恢复到正常水平。红细胞与血浆ＳＯＤ活力变化呈负相关（γ＝－０．７１６，ｐ＜０．０１）。比较ＮＨＬ和ＨＤ无论红细胞还是血浆ＳＯＤ活力变化均无显著差异（Ｐ均＞０，０５）。Ⅲ、Ⅳ期病人ＳＯＤ活力变化较Ｉ、Ⅱ期病人明显（Ｐ＜０．０５）。以上结果提示自由基损伤参与了ＭＬ的发生、发展及转归过程，且与病情的严重程度有关。     

Manganese superoxide dismutase as a diagnostic marker for malignant pleural mesothelioma

Although several immunohistochemical markers are available, differential diagnosis between mesothelioma and metastatic adenocarcinoma of the pleura is difficult. We have found that the immunoreactivity of manganese superoxide dismutase (MnSOD), an important antioxidant enzyme, is high in mesothelioma compared to healthy pleural mesothelium. The aim of the present study was to investigate whether MnSOD can be used in the differential diagnosis of malignant mesothelioma and metastatic adenocarcinoma of the pleura. MnSOD expression was assessed by using immunohistochemistry in biopsies of malignant mesothelioma (n = 35) and metastatic adenocarcinoma of the pleura (n = 21). MnSOD immunoreactivity was assessed semiquantitatively with and without microwave pretreatment. Fifteen of the 35 malignant mesotheliomas showed moderate or strong MnSOD expression without and 23 with microwave pretreatment, the corresponding figures for metastatic adenocarcinoma of the pleura being 1 and 2 out of 21 (P = 0.002 and P < 0.001, respectively by Fisher's exact test). Only mesothelioma biopsies showed strong MnSOD reactivity, and it was never negative in mesothelioma, whereas one-third of the adenocarcinomas showed no MnSOD reactivity. In conclusion, MnSOD immunoreactivity can, combined with other markers, aid the differential diagnosis between malignant mesothelioma and metastatic adenocarcinoma of the pleura.     

Role of manganese superoxide dismutase on growth and invasive properties of human estrogen-independent breast cancer cells

Manganese superoxide dismutase (MnSOD) is known to play a role in cancer. MnSOD exerts a tumor suppressive effect in estrogen-dependent human breast cancer cells. In the present study we investigated the in vitro role of MnSOD in the growth of some aggressive and highly metastatic estrogen-independent breast cancer cells, i.e., MDA-MB231 and SKBR3 cells. We show that estrogen-independent cells expressed a significantly higher basal MnSOD level compared to estrogen-dependent human breast cancer cell lines (MCF-7 and T47D). For MDA-MB231 cells, the high-MnSOD level was accompanied by an overproduction of intracellular hydrogen peroxide (H₂O₂) and by a low expression of the major H₂O₂-detoxifying enzymes, catalase, and peroxiredoxin 3, compared to MCF-7 cells. Suppression of MnSOD expression by antisense RNA was associated with a decrease of H₂O₂ content and caused a stimulation of growth with a reduced cell doubling time but induced a decrease of colony formation. Furthermore, treatment of MDA-MB231 cells with H₂O₂ scavengers markedly reduced tumor cell growth and colony formation. In addition, MnSOD suppression or treatment with H₂O₂ scavengers reduced the invasive properties of MDA-MB231 cells up to 43%, with a concomitant decrease of metalloproteinase-9 activity. We conclude that MnSOD plays a role in regulating tumor cell growth and invasive properties of estrogen-independent metastatic breast cancer cells. These action are mediated by MnSOD-dependent H₂O₂ production. In addition, these results suggest that MnSOD up-regulation may be one mechanism that contributes to the development of metastatic breast cancers.     

Differential expression of manganese superoxide dismutase, copper/zinc superoxide dismutase, and catalase in gastric adenocarcinoma and normal gastric mucosa.

AIMS: The biologic significance of antioxidant enzymes (AOEs) in gastric adenocarcinoma is still unclear. The aims of this study was to investigate the differential expression of AOEs in gastric carcinoma cells and non-cancerous counterparts and the relationship with the various clinicopathologic variables in gastric cancer patients. METHODS: Expression status of MnSOD, Cu/ZnSOD, and catalase was evaluated immunohistochemically in 120 paired gastric cancer and adjacent non-cancerous tissue. The tissues were fixed in absolute methanol immediately after surgical resection and immunohistochemistry was performed by microprobe system using tissuemicroarray slides. RESULTS: All AOEs revealed moderate to strong immunoreactivity in the parietal and intestinal metaplastic cells. Stromal cells in both cancer and non-cancerous tissue expressed MnSOD and catalase but Cu/ZnSOD. Immunoreactivity of MnSOD and catalase was increased in gastric carcinoma cells compared to their non-cancerous counterparts and revealed an association with intestinal type adenocarcinomas whereas immunoreactivity of Cu/ZnSOD did not reveal significant difference between cancer and non-cancerous mucosal cells. CONCLUSIONS: Expression of MnSOD, Cu/ZnSOD, catalas in gastric cancer cells and non-cancerous counterparts was different and increased MnSOD and possibly catalase may in part be responsible for the increased risk of intestinal type adenocarcinoma of the stomach.     

乳晕外缘环形切口在乳腺良性疾病中的应用

目的:探讨一种治疗乳腺良性疾病的美容切口的应用效果。方法:回顾性分析乳晕外缘环形切口治疗乳腺良性疾病102例的应用情况,术后效果等。结果:共治疗乳房肿块45例、乳头溢液55例、男性乳房发育2例,手术效果满意,瘢痕不明显,无并发症。结论:乳晕外缘环形切口应用于乳腺良性疾病手术是可行的,能取得治疗及美容双重效果。     

Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma

Individual response to oxidative stress, due to exposure to asbestos fibres plays a significant role in the malignant pleural mesothelioma (MPM) etiology. The differential impact on MPM risk of polymorphic alleles of glutathione-S-transferases (GSTs) and manganese superoxide dismutase (MnSOD/SOD2) genes involved in the defence against oxidative damage has been investigated. Ninety cases of MPM and 395 controls were genotyped using the arrayed-primer extension technique. Logistic regression analysis was applied to assess the predictive role of single nucleotide polymorphisms (SNPs) potentially involved in MPM carcinogenesis after adjustment for potential confounders. An increased risk of MPM was found in subjects bearing a GSTM1 null allele (OR = 1.69, 95% CI = 1.04-2.74; p = 0.034), and in those with the Ala/Ala genotypes at codon 16 within MnSOD (OR = 3.07, 95% CI = 1.55-6.05; p = 0.001). A stronger effect of MnSOD was observed among patients without a clear exposure to asbestos fibres. No effect was found for GSTA2, GSTA4, GSTM3, GSTP1 and GSTT1 genes. These findings, if replicated, contribute substantial evidence to the hypothesis that oxidative stress and cellular antireactive oxygen species systems are involved in the pathogenesis and in the natural history of MPM.     

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma

BACKGROUND: Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity. METHODS: One hundred twenty-two patients with pancreatic cancer and 331 age- and sex-matched controls were analyzed for polymorphisms of the MPO - guanine 463 adenine (-G463A) and the SOD2 alanine (Ala)-to-valine (Val) polymorphism at codon 16 (Ala16Val) genes. Cases and controls were analyzed for associations between these polymorphisms, adjusting for sex, age, history of alcohol use and smoking history. RESULTS: The variant A allele of MPO -G463A was associated with a lower risk of pancreatic cancer (adjusted odds ratio [OR] for pancreatic cancer, 0.57; 95% confidence interval [95% CI], 0.4-0.9; P = .02). The SOD2 homozygous variant genotype (Val/Val) was associated with a greater risk of pancreatic cancer (adjusted OR, 1.96; 95% CI, 1.0-3.8; P = .04). Compared with individuals who carried both low-risk alleles (A/- and Ala/-), significantly more cases than controls carried both high-risk genotypes (G/G and Val/Val; adjusted OR, 4.31; 95% CI, 1.8-10; P = .001), or 1 high-risk genotype (adjusted OR, 1.96; 95% CI, 1.1-3.4; P = .01). CONCLUSIONS: Polymorphisms of the inflammatory pathway genes MPO -G463A and SOD2 Ala16Val are associated with elevated pancreatic cancer risk. Oxidative stress may play an important role in pancreatic cancer carcinogenesis.     

血清超氧化物歧化酶和结直肠癌患者营养水平的关联性分析

目的:探讨血清超氧化物歧化酶（SOD）和结直肠癌患者营养水平的相关性。方法:选取2015年7月至2018年7月间,我院收治的结直肠癌患者120例和肠道息肉患者86例病例资料。比较两组患者血清SOD水平和总蛋白（TP）、白蛋白（ALB）、前白蛋白（PA)、血红蛋白（HGB）、淋巴细胞（LY）等营养指标,多因素分析结直肠癌患者营养水平下降的危险因素,并分析血清SOD水平与各营养指标之间的关系。结果:肠息肉组患者SOD、ALB、HGB、LY指标均明显高于结直肠癌组患者（P＜0.05）;结直肠癌NRS评分<3分的患者SOD、ALB、HGB指标均明显高于NRS评分=3分的患者（P＜0.05）;低SOD、低ALB、低HGB为结直肠癌患者营养状况下降的危险因素（P＜0.05）。相关分析显示,结直肠癌患者血清TP、ALB、PA、HGB、LY等指标与SOD水平均呈正相关（P＜0.05）。结论:结直肠癌患者血清SOD和营养状况明显下降,且疾病分期越晚下降幅度越大。患者营养状况与血清SOD水平呈正相关。     

Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.     

Manganese superoxide dismutase Ala-9Val polymorphism, environmental modifiers, and risk of breast cancer in a German population

Objective A functional polymorphism at codon 16 (Alanine-to-Valine) of manganese superoxide dismutase (MnSOD) has been hypothesized to increase the risk of breast cancer and to modify the effects of oxidative stress. However, study findings have been inconsistent and sample sizes often small. Methods We used a large population-based age-matched case–control study in German Caucasian women up to age 50 to assess breast cancer risk associated with this polymorphism and to investigate interaction with other known risk factors related to oxidative stress, including alcohol intake, cigarette smoking, and diet. Data on a total of 614 cases and 1,080 controls were evaluated using multivariate conditional logistic models. Results No main effect between genotype and breast cancer was observed. However, risk was significantly increased for Ala carriers who consumed ≥19 g of alcohol per day, compared to women homozygous for the Val allele who did not drink (OR 2.1, 95% CI 1.1–3.9; p = 0.13 for interaction). No significant effect modification was observed for smoking or diet. Conclusions The MnSOD Ala-9Val polymorphism may contribute to an increase in breast cancer risk in the context of high alcohol consumption, however the polymorphism is not an overall risk factor for breast cancer in this primarily premenopausal population. This work was supported by the Medical Faculty of the University of Ulm (P.589 and P.685) and the Deutsche Krebshilfe e.V. (Project number 70492)     

COX-2和VEGF-C基因在乳腺良恶性病变中的表达研究

目的 研究COX-2和VEGF-C mRNA在乳腺良恶性病变中的表达情况,探讨两者在乳腺肿瘤发生过程中的相互关系.方法 运用Real-time PCR方法对90例乳腺良恶性病变组织中COX-2和VEGF-C mRNA的表达进行检测.结果 8例副乳腺组织中,COX-2和VEGF-C mRNA不表达或低表达,15例腺病和16例纤维腺瘤中两者表达明显增加(P＜0.05),11例DCIS中,两者均高表达,高于腺病和纤维腺瘤(P＜0.05),40例IDC中,两者同样高表达,并且肿瘤级别越高,表达水平越高.在DCIS和IDC中,两者表达存在正相关关系(分别r=0.82,P=0.002;r=0.89,P=0.000).结论 COX-2和VEGF-C基因在乳腺良恶性病变中表达明显增高,而且在恶性肿瘤中的表达高于良性肿瘤,两者在乳腺癌组织中的表达呈正相关,表明两者参与了乳腺疾病,尤其是乳腺癌发生、发展的过程.     

Acetylation at lysine 71 inactivates superoxide dismutase 1 and sensitizes cancer cells to genotoxic agents

Cancer cells are characterized by a high dependency on antioxidant enzymes to cope with the elevated rates of reactive oxygen species (ROS). Impairing antioxidant capacity in cancer cells disturbs the ROS homeostasis and exposes cancer cells to massive oxidative stress. In this study, we have discovered that superoxide dismutase 1 (SOD1), a major player in maintaining the cellular redox status, was acetylated at lysine 71. This acetylation, which was primarily deacetylated by Sirtuin 1 (SIRT1), suppressed the enzymatic activity of SOD1 via disrupting its association with copper chaperone for SOD1 (CCS). More importantly, genotoxic agents, such as camptothecin (CPT), induced SOD1 acetylation by disrupting its binding with SIRT1. CPT-induced SOD1 acetylation was stimulated by its provoked ROS, suggesting a positive feedback loop, in which ROS per se impairs the antioxidative defence of cancer cells and reinforces oxidative stress stimulated by anticancer agents. The intrinsic abundance of SOD1 acetylation varied among cancer cells, and high level of SOD1 acetylation was correlated with elevated sensitivity to CPT. Together, our findings gained mechanistic insights into how cytotoxic agents fine tune the intracellular ROS homeostasis to strengthen their anticancer effects, and suggested SOD1 acetylation as a candidate biomarker for predicting response to CPT-based chemotherapy.     

Changes in benign to malignant ratio of surgically treated breast diseases in a district hospital

The benign to malignant ratio (BMR) of open surgical biopsies is often used to monitor the efficacy of diagnostic workup of breast lesions. Avoiding the unnecessary removal of benign lesions is of recognized importance. Histopathology archives of the Department of Pathology of the Bács-Kiskun County Hospital were retrieved for breast lesions and the BMR of surgical specimens was determined for each year between the period of 1965–1996. The introduction of mammography and especially fine-needle aspiration cytology was paralleled by a reduction in the benign to malignant ratio from 1.7 to 0.7. Only the introduction of breast aspiration cytology seemed to have a significant effect on the BMR, but the more adequate diagnostic approach to breast lesions (mostly palpable in their nature) was in part masqueraded by the late shift in attitude of both surgeons and patients towards breast lumps. This is why the BMR can give a basic information on preoperative diagnostic workup of breast lesions, but in itself it is not able to monitor them.