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1.
Chemistry ; 27(34): 8865-8874, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-33871121

RESUMO

Human telomeric DNA, in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine (8oxoG) lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

2.
J Proteome Res ; 19(11): 4291-4315, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33119313

RESUMO

The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.


Assuntos
Antivirais , Infecções por Coronavirus , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Simulação de Dinâmica Molecular , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus
4.
Dalton Trans ; 49(33): 11451-11466, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32776052

RESUMO

In this perspective, we discuss iron-complexes as drug candidates that are promising alternatives to conventional platinum-based chemotherapies owing to their broad range of reactivities and to the targeting of different biological systems. Breakthroughs in the comprehension of iron complexes' structure-activity relationship contributed to the clarification of their metabolization pathways, sub-cellular localization and influence on iron homeostasis, while enlightening the primary molecular targets of theses likely multi-target metallodrugs. Both the antiproliferative activity and elevated safety index observed among the family of iron complexes showed encouraging results as per their therapeutic potential and selectivity also with the aim of reducing chemotherapy side-effects, and facilitated more pre-clinical investigations. The purpose of this perspective is to summarize the recent advances that contributed in unveiling the intricate relationships between the structural modifications on iron-complexes and their reactivity, cellular trafficking and global mechanisms of action to broaden their use as anticancer drugs and advance to clinical evaluation.

5.
Sci Rep ; 10(1): 13750, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792639

RESUMO

Glioblastoma (GBM) is one of the most aggressive types of cancer, which begins within the brain. It is the most invasive type of glioma developed from astrocytes. Until today, Temozolomide (TMZ) is the only standard chemotherapy for patients with GBM. Even though chemotherapy extends the survival of patients, there are many undesirable side effects, and most cases show resistance to TMZ. FL3 is a synthetic flavagline which displays potent anticancer activities, and is known to inhibit cell proliferation, by provoking cell cycle arrest, and leads to apoptosis in a lot of cancer cell lines. However, the effect of FL3 in glioblastoma cancer cells has not yet been examined. Hypoxia is a major problem for patients with GBM, resulting in tumor resistance and aggressiveness. In this study, we explore the effect of FL3 in glioblastoma cells under normoxia and hypoxia conditions. Our results clearly indicate that this synthetic flavagline inhibits cell proliferation and induced senescence in glioblastoma cells cultured under both conditions. In addition, FL3 treatment had no effect on human brain astrocytes. These findings support the notion that the FL3 molecule could be used in combination with other chemotherapeutic agents or other therapies in glioblastoma treatments.

6.
J Phys Chem Lett ; 11(14): 5661-5667, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32536162

RESUMO

Coronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible for the global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting the SARS viruses to bypass the host protective response. This work also constitutes a first step in the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus.


Assuntos
Betacoronavirus/química , Betacoronavirus/genética , Infecções por Coronavirus/virologia , Quadruplex G/efeitos dos fármacos , Pneumonia Viral/virologia , RNA Viral/química , RNA Viral/genética , Betacoronavirus/efeitos dos fármacos , Dimerização , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Pandemias , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
7.
Mar Drugs ; 18(4)2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32295082

RESUMO

Breast cancer is the leading cause of death from cancer among women. Higher consumption of dietary marine n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) is associated with a lower risk of breast cancer. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two n-3 LC-PUFAs found in fish and exert anticancer effects. In this study, natural marine- derived lecithin that is rich in various polyunsaturated fatty acids (PUFAs) was extracted from salmon heads and transformed into nanoliposomes. These nanoliposomes were characterized and cultured with two breast cancer lines (MCF-7 and MDA-MB- 231). The nanoliposomes decreased the proliferation and the stiffness of both cancer cell types. These results suggest that marine-derived lecithin possesses anticancer properties, which may have an impact on developing new liposomal delivery strategies for breast cancer treatment.


Assuntos
Antineoplásicos/química , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Peixes , Lipossomos/química , Animais , Antineoplásicos/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Feminino , Humanos , Lipossomos/farmacologia , Células MCF-7/efeitos dos fármacos
8.
Eur J Med Chem ; 187: 111939, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838327

RESUMO

Breast cancer is a major medical threat which cannot be sufficiently addressed by current therapies because of spontaneous or acquired treatment resistance. Besides, triple-negative breast cancer (TNBC) tumors do not respond to targeted therapies, thus new therapeutic strategies are needed. In this context, we designed and prepared new desulfured troglitazone (TGZ)-derived molecules and evaluated them in vitro for their anti-proliferative activity, with a special focus on triple-negative breast cancer cell lines. Optimization of the synthetic strategies and deracemization of the lead compound were performed to give highly active compound 10 with low-micromolar potency. Further studies revealed that this compound triggers apoptosis rather than cell cycle arrest as observed with TGZ.


Assuntos
Antineoplásicos/farmacologia , Troglitazona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Troglitazona/síntese química , Troglitazona/química
9.
J Phys Chem B ; 123(34): 7365-7371, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365827

RESUMO

The behavior of the structural parameters of DNA considering different levels of methylation in CpG islands is studied by means of full-atom molecular dynamics simulations and electronic circular dichroism, both in an artificial model system and in a gene promoter sequence. It is demonstrated that methylation although intrinsically brings quite local perturbations may, if its level is high enough, induce cooperative effects that strongly modify the DNA backbone torsional parameters altering the helicity as compared to the nonmethylated case. Because methylation of the CpG island is correlated with the regulation of gene expression, understanding the structural modifications induced in DNA is crucial to characterize all the fine equilibria into play in epigenetics phenomena.


Assuntos
Citosina/química , Metilação de DNA , DNA/química , Ilhas de CpG , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico
10.
J Appl Toxicol ; 39(5): 764-772, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30605223

RESUMO

Human exposure to airborne carbon nanotubes (CNT) is increasing because of their applications in different sectors; therefore, they constitute a biological hazard. Consequently, developing studies on CNT toxicity become a necessity. CNTs can have different properties in term of length, size and charge. Here, we compared the cellular effect of multiwall (MWCNTs) and single wall CNTs (SWCNTs). MWCNTs consist of multiple layers of graphene, while SWCNTs are monolayers. The effects of MWCNTs and SWCNTs were evaluated by the water-soluble tetrazolium salt cell proliferation assay on NR8383 cells, rat alveolar macrophage cell line (NR8383). After 24 hours of exposure, MWCNTs showed higher toxicity (50% inhibitory concentration [IC50 ] = 3.2 cm2 /cm2 ) than SWCNTs (IC50  = 44 cm2 /cm2 ). Only SWCNTs have induced NR8383 cells apoptosis as assayed by flow cytometry using the annexin V/IP staining test. The expression of genes involved in oxidative burst (Ncf1), inflammation (Nfκb, Tnf-α, Il-6 and Il-1ß), mitochondrial damage (Opa) and apoptotic balance (Pdcd4, Bcl-2 and Casp-8) was determined. We found that MWCNT exposure predominantly induce inflammation, while SWCNTs induce apoptosis and impaired mitochondrial function. Our results clearly suggest that MWCNTs are ideal candidates for acute inflammation induction. In vivo studies are required to confirm this hypothesis. However, we conclude that toxicity of CNTs is dependent on their physical and chemical characteristics.


Assuntos
Poluentes Atmosféricos/toxicidade , Macrófagos Alveolares/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Poluentes Atmosféricos/química , Animais , Linhagem Celular , Nanotubos de Carbono/química , Tamanho da Partícula , Ratos , Propriedades de Superfície
12.
Sci Rep ; 7(1): 8885, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827702

RESUMO

Nonsteroidal 2-arylproprionic acids are widely used, over-the-counter, anti-inflammatory drugs. Photosensitivity is a commonly overlooked adverse effect of these drugs. Based on the combined use of cell viability assays and molecular modeling, we prove and rationalize the photochemical pathways triggering photosensitization for two drugs, ibuprofen and ketoprofen. As its parent compound benzophenone, ketoprofen produces singlet oxygen, upon triplet manifold population. However, ibuprofen and ketoprofen photodissociate and hence may generate two highly reactive radicals. The formation of metastable aggregates between the two drugs and B-DNA is also directly probed by molecular dynamics. Our approach characterizes the coupled influence of the drug's intrinsic photochemistry and the interaction pattern with DNA. The photosensitization activity of nonsteroidal 2-arylproprionic acids, being added to gels and creams for topical use, should be crucially analyzed and rationalized to enact the proper preventive measures.


Assuntos
Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Ibuprofeno/farmacologia , Cetoprofeno/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Raios Ultravioleta , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Ibuprofeno/química , Cetoprofeno/química , Modelos Moleculares , Estrutura Molecular , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade , Raios Ultravioleta/efeitos adversos
13.
Breast Cancer Res Treat ; 165(3): 517-527, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28681173

RESUMO

PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "claudin-1-low" TNBC cells, Δ2-TGZ treatment induced claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced claudin-1 expression in both the cells. In absence of claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that claudin-1 re-expression could be an interesting therapeutic strategy for "claudin-1-low" TNBC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Claudina-1/metabolismo , Ésteres do Ácido Sulfúrico/farmacologia , Tiazolidinedionas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Apoptose/genética , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Claudina-1/genética , Feminino , Regulação da Expressão Gênica , Humanos , Transporte Proteico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Troglitazona
14.
J Phys Chem B ; 121(32): 7586-7592, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28735538

RESUMO

We report a combined computational and experimental study to rationalize the behavior of a well-known singlet oxygen (1O2) probe, that is, the chromophore of the Singlet Oxygen Sensor Green: a fluoresceine-based sensor. In particular, we evidence that the presence of an intramoleculer charge transfer state that is no more present upon reaction with 1O2 explains the fluorescence enhancement observed in the presence of reactive oxygen species. Furthermore, we also unequivocally show the photophysical pathways leading to the fluorescence enhancement of fluoresceine upon irradiation with UVA lights and also in the absence of any oxygen activator. More specifically, we evidence that the presence of a possible intersystem crossing upon population of higher energy singlet electronic excited states will lead to the population of the fluoresceine triplet manifold and hence to the self-production of 1O2.

15.
Cell Cycle ; 15(24): 3402-3412, 2016 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-27753533

RESUMO

We have previously shown that Δ2-Troglitazone (Δ2-TGZ) displayed anticancer effects on breast cancer cell lines grown in low serum conditions (1% fetal calf serum (FCS)). The present study was performed in order to characterize the effects of Δ2-TGZ in high serum containing medium and to determine if starvation could influence the response of breast cancer cells to this compound, keeping in mind the potential interest for breast cancer therapy. We observed that in high serum conditions (10% FCS), a 48 h treatment with Δ2-TGZ induced a decrease in cell numbers in MDA-MB-231 and MCF-7 breast cancer cell lines. The IC50 values were higher than in low serum conditions. Furthermore, in contrast to our previous results obtained in 1% FCS conditions, we observed that in 10% FCS-containing medium, MCF-7 cells were more sensitive to Δ2-TGZ than MDA-MB-231 cells. Δ2-TGZ also induced endoplasmic reticulum (ER) stress mainly in MDA-MB-231 cells. Besides, in high serum conditions, Δ2-TGZ induced a G0/G1 cell cycle arrest, an inhibition of BrdU incorporation and a reduced level of cyclin D1. We observed a limited cleavage of PARP and a limited proportion of cells in sub-G1 phase. Thus, in high serum conditions, Δ2-TGZ displayed cytostatic effects rather than apoptosis as previously reported in 1% FCS-containing medium. Our results are in accordance with studies suggesting that serum starvation could potentiate the action of diverse anti-cancer agents.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Cromanos/farmacologia , Soro/metabolismo , Tiazolidinedionas/farmacologia , Contagem de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Fator de Transcrição CHOP/metabolismo , Troglitazona , Células Tumorais Cultivadas
16.
Sci Rep ; 6: 28480, 2016 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-27329409

RESUMO

We report a molecular modeling study, coupled with spectroscopy experiments, on the behavior of two well known organic dyes, nile blue and nile red, when interacting with B-DNA. In particular, we evidence the presence of two competitive binding modes, for both drugs. However their subsequent photophysical behavior is different and only nile blue is able to induce DNA photosensitization via an electron transfer mechanism. Most notably, even in the case of nile blue, its sensitization capabilities strongly depend on the environment resulting in a single active binding mode: the minor groove. Fluorescence spectroscopy confirms the presence of competitive interaction modes for both sensitizers, while the sensitization via electron transfer, is possible only in the case of nile blue.


Assuntos
DNA de Forma B/química , Oxazinas/química , Fármacos Fotossensibilizantes/química , Sítios de Ligação , Ligação Competitiva , Simulação por Computador , Transporte de Elétrons , Corantes Fluorescentes/química , Modelos Moleculares , Conformação de Ácido Nucleico , Processos Fotoquímicos , Polidesoxirribonucleotídeos/química , Espectrometria de Fluorescência , Espectrofotometria
17.
Nanoscale ; 8(9): 5268-79, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26879405

RESUMO

DDB2, known for its role in DNA repair, was recently shown to reduce mammary tumor invasiveness by inducing the transcription of IκBα, an inhibitor of NF-κB activity. Since cellular adhesion is a key event during the epithelial to mesenchymal transition (EMT) leading to the invasive capacities of breast tumor cells, the aim of this study was to investigate the role of DDB2 in this process. Thus, using low and high DDB2-expressing MDA-MB231 and MCF7 cells, respectively, in which DDB2 expression was modulated experimentally, we showed that DDB2 overexpression was associated with a decrease of adhesion abilities on glass and plastic areas of breast cancer cells. Then, we investigated cell nanomechanical properties by atomic force microscopy (AFM). Our results revealed significant changes in the Young's Modulus value and the adhesion force in MDA-MB231 and MCF7 cells, whether DDB2 was expressed or not. The cell stiffness decrease observed in MDA-MB231 and MCF7 expressing DDB2 was correlated with a loss of the cortical actin-cytoskeleton staining. To understand how DDB2 regulates these processes, an adhesion-related gene PCR-Array was performed. Several adhesion-related genes were differentially expressed according to DDB2 expression, indicating that important changes are occurring at the molecular level. Thus, this work demonstrates that AFM technology is an important tool to follow cellular changes during tumorigenesis. Moreover, our data revealed that DDB2 is involved in early events occurring during metastatic progression of breast cancer cells and will contribute to define this protein as a new marker of metastatic progression in this type of cancer.


Assuntos
Neoplasias da Mama , Proteínas de Ligação a DNA/biossíntese , Módulo de Elasticidade , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/ultraestrutura , Adesão Celular , Feminino , Humanos , Células MCF-7 , Microscopia de Força Atômica , Metástase Neoplásica
18.
Front Chem ; 3: 67, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26734600

RESUMO

We report the characterization of the interaction between B-DNA and three terpyridin iron II complexes. Relatively long time-scale molecular dynamics (MD) is used in order to characterize the stable interaction modes. By means of molecular modeling and UV-vis spectroscopy, we prove that they may lead to stable interactions with the DNA duplex. Furthermore, the presence of larger π-conjugated moieties also leads to the appearance of intercalation binding mode. Non-covalent stabilizing interactions between the iron complexes and the DNA are also characterized and evidenced by the analysis of the gradient of the electronic density. Finally, the structural deformations induced on the DNA in the different binding modes are also evidenced. The synthesis and chemical characterization of the three complexes is reported, as well as their absorption spectra in presence of DNA duplexes to prove the interaction with DNA. Finally, their effects on human cell cultures have also been evidenced to further enlighten their biological effects.

19.
Mol Pharm ; 12(2): 554-61, 2015 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-25536094

RESUMO

S-Nitrosoglutathione (GSNO) is a good candidate for nitric oxide (NO(•)) delivery, and its nanoformulation improves NO(•) stability and bioavailability. We have compared the effect of empty Eudragit nanoparticles (eENP), GSNO-loaded ENP (gENP), and free GSNO on THP-1 human monocytic cell line. We investigated cellular viability and growth by WST-1 and trypan blue tests. ENP uptake was studied using transmission electron microscopy, confocal microscopy, and flow cytometry. Transcriptomic profiles were obtained using microarray. ENP entered cells by clathrin- and caveolae-mediated endocytosis. Exposure to either free GSNO or gENP induced an activation of genes from the same clusters, in favor of intracellular delivery of GSNO by ENP. GSNO nanoformulation might be a therapeutic option for NO(•) delivery.


Assuntos
Monócitos/metabolismo , Nanopartículas/química , S-Nitrosoglutationa/química , S-Nitrosoglutationa/metabolismo , Linhagem Celular , Endocitose/fisiologia , Humanos , Microscopia Eletrônica de Transmissão , Monócitos/ultraestrutura , Óxido Nítrico/metabolismo , Transcriptoma/genética
20.
Free Radic Biol Med ; 77: 139-51, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25224035

RESUMO

Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently reliable predictive biological markers, and this is a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation, which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O2(•-)) and hydrogen peroxide (H2O2). Particularly, they report how these reactive oxygen species may activate some signaling pathways involved in breast tumor growth. Emerging understanding of these findings provides an interesting framework for guiding translational research and suggests a way to define precisely the clinical interest of MnSOD as a prognostic and/or predicting marker in breast cancer, by associating with some regulators involved in SOD2 gene regulation and other well-known biomarkers, in addition to the typical clinical parameters.


Assuntos
Neoplasias da Mama/enzimologia , Superóxido Dismutase/fisiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células , Indução Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Estresse Oxidativo , Polimorfismo Genético , Superóxidos/metabolismo
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