RESUMO
In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Glândulas Mamárias Humanas/patologia , Estresse Oxidativo , Adulto , Idoso , Área Sob a Curva , Mama/metabolismo , Neoplasias da Mama/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Homocisteína/análise , Humanos , Peroxidação de Lipídeos , Malondialdeído/análise , Glândulas Mamárias Humanas/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/análise , Carbonilação Proteica , Curva ROC , Fator de Necrose Tumoral alfa/análiseRESUMO
Trastuzumab is an immunotargeting therapeutic against breast tumors with amplification of the human epithelial growth factor receptor 2 (HER2). HER2 patients naturally exhibit disruption in the pro-oxidant inflammatory profiling; however, the impact of trastuzumab-based chemotherapy in modulating this process is still unknown. Here we determined the systemic pro-inflammatory profile of women diagnosed with HER2-amplified tumors, undergoing trastuzumab-based chemotherapy (TZ), and compared the results with that of healthy controls (CTR) and untreated patients with HER2-amplified breast cancer (CA). The plasmatic inflammatory profile was assessed by evaluating pro-oxidant parameters such as lipid peroxidation, total antioxidant capacity (TRAP), levels of advanced oxidation protein products (AOPPs), nitric oxide (NO), C-reactive protein (CRP), and total thiol content. Markers of cardiac damage were also assessed. Our findings showed increased NO levels in TZ than that in either CA or CTR groups. Furthermore, TZ augmented TRAP and reduced total thiol than that of the CA group. Our data also revealed that AOPP levels were significantly higher in the TZ than the CA group. AOPP and the MB fraction of creatine-kinase (CKMB) levels were positively correlated in TZ patients. These findings suggest that trastuzumab-associated chemotherapy can modulate the pro-inflammatory markers of HER2-positive breast cancer patients to the levels found in healthy controls.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Tratamento Farmacológico , Trastuzumab/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Proteína C-Reativa/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Óxido Nítrico/metabolismo , Oxirredução/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Compostos de Sulfidrila/metabolismo , Trastuzumab/efeitos adversosRESUMO
Nitric oxide (NO) levels increase considerably after 24h of exposure of skin to ultraviolet B (UVB) radiation, which leads to nitrosative skin injury. In addition, increased NO levels after exposure to UVB radiation are associated with inhibition of cell proliferation. Compared to the UV-control group, UV-genistein at 10 mg/kg (UV-GEN10) group showed tissue protection, decreased lipid peroxide and nitrotyrosine formation, and low CAT activity. Furthermore, NO levels and iNOS labeling remained high. In this group, the reduction in lipid peroxides and nitrotyrosine was accompanied by upregulation of cell proliferation factors (Ki67 and PCNA), which indicated that prevention of nitrosative skin injury promoted cell proliferation and DNA repair. Genistein also prevented nitrosative events, inhibited ONOO(-) formation, which leads to tissue protection and cell proliferation. The UV-GEN15 group did not result in a greater protective effect compared to that with UV-GEN10 group. In the UV-GEN15 group, histological examination of the epidermis showed morphological alterations without efficient protection against lipid peroxide formation, as well as inhibition of Ki67 and PCNA, and VEGF labeling, which suggested inhibition of cell proliferation. These results help to elucidate the mechanisms underlying the photoprotective effect of genistein and reveal the importance of UVB radiation-induced nitrosative damage.
Assuntos
Genisteína/farmacologia , Protetores contra Radiação/farmacologia , Pele/efeitos dos fármacos , Pele/lesões , Raios Ultravioleta/efeitos adversos , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Antígeno Ki-67/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Recent works have shown a dual side of estrogens, and research on the relationship between oxidative stress and menopausal status remains unclear and has produced controversial results. In this work, we aimed to evaluate by sensitive methods the oxidant and antioxidant changes that develop after natural menopause. Thirty premenopausal and 28 naturally postmenopausal women volunteered for this study. Blood was collected and plasma used. 17-OH estradiol levels in plasma were estimated. Plasma levels of advanced oxidation protein products (AOPP), lipid peroxidation products (such as hydroperoxides and malondialdehyde (MDA)), and nitrites were measured, and total radical antioxidant parameter testing was performed to determine the oxidant and antioxidant profiles, respectively. Estrogen levels were significantly increased (p < 0.02) in premenopausal women (54.28 ± 9.34 pg/mL) as compared with postmenopausal women (18.10 ± 1.49 pg/mL). Postmenopausal women had lower levels of lipid hydroperoxide oxidation (p < 0.0001), lipid hydroperoxide levels evaluated by the area under the curve (AUC; 1,366,000 ± 179,400 AUC; p < 0.01), and hydroperoxides as measured by the ferrous oxidation-xylenol orange method (31.48 ± 2.7 µM; p < 0.0001). The MDA levels did not differ between pre- and postmenopausal women whether measured by thiobarbituric acid-reactive substances or high-performance liquid chromatography assays. No differences in AOPP and nitrite levels were observed between pre- and postmenopausal women. Postmenopausal women also exhibited a higher total radical antioxidant level (0.89 ± 0.08 µM Trolox; p < 0.0001). Postmenopausal women demonstrated lower levels of oxidative damage and a higher antioxidant capacity than premenopausal women.
Assuntos
Produtos da Oxidação Avançada de Proteínas/sangue , Antioxidantes/metabolismo , Oxidantes/sangue , Estresse Oxidativo/fisiologia , Pós-Menopausa/sangue , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Seguimentos , Humanos , Peróxido de Hidrogênio/sangue , Peroxidação de Lipídeos , Malondialdeído/sangue , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Breast cancer consists in a chronic inflammatory disease with multiple biological and clinical behaviors. Based on high throughput technologies data, this disease is currently classified according to the molecular expression of estrogen (ER), progesterone (PR) and human epidermal growth factor (HER-2) receptors. In this study, we defined the inflammatory profile of the main molecular subtypes of breast cancer patients: luminal (ER and PR positive, HER-2 negative), HER-2 enriched (HER-2 positive) and triple negative (ER, PR and HER-2 negative). Cytokines panel was assessed by measurement of TNF-α, TGF-ß, IL-1, IL-10 and IL-12 plasmatic levels. Oxidative profile was assessed by determination of lipid peroxidation, total antioxidant capacity of plasma, malondialdehyde levels, carbonyl content and nitric oxide (NO). Clinical data were correlated with inflammatory findings. Our findings demonstrated that patients bearing the luminal subtype displayed high TNF-α, TGF-ß and enhanced oxidative stress levels associated with reduced IL-12. HER-2-enriched group exhibited higher levels of TNF-α, IL-12 and TGF-ß associated with enhanced oxidative stress. Triple-negative subtype exhibited the most aggressive profile of disease behavior, with reduction in both TNF-α and TGF-ß, with high levels of lipid peroxidation and NO. The clinical importance of our findings lies in the fact that the inflammatory status varies in distinct ways due to molecular subtype of breast cancer, opening potential therapeutic targets to future therapies.
Assuntos
Neoplasias da Mama/patologia , Inflamação/patologia , Adulto , Antineoplásicos/uso terapêutico , Antioxidantes/análise , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/imunologia , Citocinas/sangue , Doxorrubicina/uso terapêutico , Feminino , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos , Malondialdeído/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica , Óxido Nítrico/sangue , Estresse Oxidativo , Paclitaxel/uso terapêutico , Prognóstico , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
This study provides evidence that skin oxidative stress injury caused by UVB irradiation is mediated predominantly by reactive oxygen species immediately after irradiation and by reactive nitrogen species at later time points. Animals were pre-treated with free radical scavengers (deferrioxamine, histidine), α-tocopherol, or inhibitors of nitric oxide synthase (NOS) (L-NAME or aminoguanidine) or left untreated and subjected to UVB irradiation. α-Tocopherol inhibited the increase in lipid peroxidation, as evaluated by chemiluminescence at 0 h and 24 h after UVB irradiation. Immediately after UVB irradiation, lipid peroxidation increased moderately and was abolished by free radical scavengers but not by NOS inhibitors. Likewise, the reduction of antioxidant capacity was not reversed by NOS inhibitors. Nitric oxide augmentation was not observed at this time point. Twenty-four hours after irradiation, increased lipid peroxidation levels and nitric oxide elevation were observed and were prevented by NOS inhibitors. Low concentrations of GSH and reduced catalase activity were also observed. Altogether, these data indicate that reactive oxygen species (singlet oxygen and hydroxyl radicals) are the principal mediators of immediate damage and that reactive nitrogen species (*NO and possibly ONOO(-)) seem to be involved later in skin oxidative injury induced by UVB radiation. The reduced catalase activity and low level of GSH suggest that *NO and H(2)O(2) may react to generate ONOO(-), a very strong lipid peroxidant species.
Assuntos
Radical Hidroxila/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos da radiação , Oxigênio Singlete/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Antioxidantes/metabolismo , Dissulfeto de Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos da radiação , Masculino , Camundongos , Pele/enzimologia , Fatores de TempoRESUMO
Several adverse effects of chemotherapy treatments have been described, and most of these effects are associated with direct interactions between blood cells and indirect effects generated during the oxidative metabolism of antineoplastic drugs. In this study we evaluated the oxidative systemic status and hematological profiles of breast cancer patients with advanced ductal infiltrative carcinoma treated with doxorubicin (DOX) or paclitaxel (PTX) within 1 h after chemotherapy. Blood analyses included evaluation of hemogram, pro-oxidative markers, and antioxidant status. The results showed that advanced breast cancer diseased (AD) patients without previous chemotherapy presented anemia and high oxidative stress status characterized by elevated levels of lipid peroxidation and nitric oxide, and reduced catalase activity when compared with controls. DOX-treated patients exhibited increased anemia and reduced antioxidant status, which was revealed by decreases in reduced glutathione levels and the total antioxidant capacity of plasma; however, these changes did not lead to further increases in lipid peroxidation or carbonyl proteins when compared with the AD group. PTX-treated patients also showed increased anemia, lactate dehydrogenase leakage, and enhanced lipid peroxidation. These data reveal for the first time that patients subjected to chemotherapy with DOX or PTX present immediate systemic oxidative stress and red blood cell oxidative injury with anemia development. These findings provide a new perspective on the systemic redox state of AD and patients subjected to chemotherapy regarding oxidative stress enhancement and its possible involvement in the aggravation of chronic anemia.
Assuntos
Neoplasias da Mama/sangue , Carcinoma Ductal de Mama/sangue , Estresse Oxidativo , Adulto , Idoso , Antioxidantes/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Catalase/metabolismo , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Feminino , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nitritos/metabolismo , Carbonilação Proteica , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Antineoplastic chemotherapy still consists in the major first-line therapeutics against cancer. Several reports have described the immunomodulatory effects of these drugs based on in vitro treatment, but no previous data are known about these effects in patients and its association with immunological-mediated toxicity. In this study, we first characterize the immunological profile of advanced breast cancer patients treated with doxorubicin and paclitaxel protocols, immediately after chemotherapy infusion. Our findings included an immediate plasmatic reduction in IL-1, IL-10, and TNF-α levels in doxorubicin-treated patients, as well as high levels of IL-10 in paclitaxel patients. Further, it was demonstrated that both drugs led to leukocytes oxidative burst impairment. In vitro analysis was performed exposing healthy blood to both chemotherapics in the same concentration and time of exposition of patients, resulting in low IL-10 and high IL-1ß in doxorubicin exposition, as low TNF-α and high IL-1 in paclitaxel treatment. Nitric oxide levels were not altered in both in vivo and in vitro treatments. In conclusion, our data revealed for the first time that the immediate effects of chemotherapy could be mediated by cytokines signaling in patients and that the results observed in patients could be a resultant of host immune cells activation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma/diagnóstico , Carcinoma/imunologia , Carcinoma/patologia , Citocinas/sangue , Doxorrubicina/efeitos adversos , Feminino , Humanos , Imunomodulação , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paclitaxel/efeitos adversosRESUMO
Breast cancer is the malignant neoplasia with the highest incidence in women worldwide. Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression. Human studies have not considered the complexity of tumor biology during the stages of cancer advance, limiting their clinical application. The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early (ED; TNM I and II) and advanced disease (AD; TNM III and IV) of patients diagnosed with infiltrative ductal carcinoma breast cancer. Oxidative stress parameters were evaluated by plasmatic lipoperoxidation, carbonyl content, thiobarbituric reactive substances (TBARS), nitric oxide levels (NO), total radical antioxidant parameter (TRAP), superoxide dismutase, and catalase activities and GSH levels. Immune evaluation was determined by TNF-α, IL-1ß, IL-12, and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence. Tissue damage analysis included heart (total CK and CKMB), liver (AST, ALT, GGT), and renal (creatinine, urea, and uric acid) plasmatic markers. C-reactive protein (CRP) and iron metabolism were also evaluated. Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages. ED was characterized by reduction in catalase, 8-isoprostanes, and GSH levels, with enhanced lipid peroxidation and TBARS levels. AD exhibited more pronounced oxidative status, with reduction in catalase activity and TRAP, intense lipid peroxidation and high levels of NO, TBARs, and carbonyl content. ED patients presented a Th2 immune pattern, while AD exhibited Th1 status. CRP levels and ferritin were increased in both stages of disease. Leukocytes burst impairment was observed in both the groups. Plasma iron levels were significantly elevated in AD. The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators.
Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Citocinas/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Peroxidação de Lipídeos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Óxido Nítrico/sangue , Oxirredução , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto JovemRESUMO
Spathodea campanulata is used in traditional medicine in Africa as diuretic and anti-inflammatory. Although few studies have reported the mechanism of antioxidant action, this study evidenced the antioxidant activity of S. campanulata bark and flower extracts and their possible mechanism of action. Ethanol extracts of S. campanulata bark and flowers showed antioxidant activity on lipid peroxidation of liver microsome induced by Fe3+-ascorbic acid. Bark extract was 5 times more efficient than flower extract. The antioxidant activity of flower extract, previously complexed with increasing concentrations of Fe3+ (20 - 100 µM) which resulted in antioxidant activity loss, was shown to be related to iron complex formation. In contrast, the antioxidant activity of bark extract was not inhibited by the previous incubation with Fe3+, although complexation was demonstrated by spectral analysis of the solution. These results suggest an antioxidant mechanism other than Fe3+ complex formation. Therefore, the antioxidant mechanisms of S. campanulata flower and bark extracts are distinct from each other, reflecting the extract heterogeneous composition and the mechanism of action.
Spathodea campanulata é usada na medicina popular na África como diurético e antiinflamatório. Embora poucos estudos relatem o mecanismo de ação antioxidante, neste trabalho foi evidenciado a atividade antioxidante dos extratos da casca e da flor da S. campanulata e o possível mecanismo de ação. Os extratos etanólicos da casca e da flor da S. campanulata mostrou possuir atividade antioxidante sobre a lipoperoxidação de microssoma hepático induzida por Fe3+-ácido ascórbico. O extrato da casca foi 5 vezes mais eficiente que da flor. O extrato da flor foi previamente complexado com concentrações crescentes de Fe3+ (20 - 100 µM) o qual resultou na perda da atividade antioxidante, demonstrando que esta está relacionada com a formação de complexo com o ferro. Por outro lado, a atividade antioxidante do extrato da casca não foi inibida pela prévia incubação com o ferro, embora haja a formação do complexo evidenciado pela análise espectral da solução. Estes resultados sugerem que o mecanismo antioxidante seja outro que não a complexação com o Fe3+. Portanto, o mecanismo antioxidante dos extratos da flor e da casca da S. campanulata é distinto entre si o que reflete a composição heterogênica do extrato e o mecanismo de ação.