Banca de DEFESA: JESSICA DUARTE SOUSA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : JESSICA DUARTE SOUSA
DATA : 03/05/2019
HORA: 13:00
LOCAL: NUTS-HUPES
TÍTULO:

Superoxide Dismutase Type 1 as a Potential Therapeutic Target for Adult T-Cell Leukemia/Lymphoma, pathology associated with Human T-cell Lymphotropic Virus Type 1 infection

PALAVRAS-CHAVES:

HTLV-1, SOD1, ATLL

PÁGINAS: 91
GRANDE ÁREA: Ciências da Saúde
ÁREA: Saúde Coletiva
SUBÁREA: Saúde Pública
RESUMO:

INTRODUCTION: Secondary treatments mechanism, such as the use of antioxidants and interferon (IFN) type 1, for the pathology associated with Human T-cell lymphotropic Virus type 1 (HTLV-1), HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), is not elucidated, but, it is based on protection against Reactive Oxygen Species (ROS). The human Superoxide Dismutase 1 (SOD1) enzyme catalyzes the dismutation of superoxide radicals and it is important for the HTLV-1 survival in the intracellular environment. Inhibitory mechanisms of this enzyme, using diethyldithiocarbamate (DETC) for example, could increase the intracellular superoxide concentration, triggering oxidative stress and inducing cell death trough apoptosis. Thus, the regulation of superoxide in infected lymphocytes through the SOD1 antioxidant activity could be a therapeutic target for Adult T-cell leukemia/lymphoma (ATLL), another pathology also associated with HTLV-1. OBJECTIVE: To investigating the antioxidant SOD1 enzyme as a potential therapeutic target for ATLL; and its inhibitor, DETC, as a promising pro-oxidant therapy for this pathology. MATERIAL AND METHODS: The Gene Expression Omnibus (GEO) database was used to the search for gene expression datasets associated with ATLL clinical forms (Indolent, chronic, lymphomatous, and acute). The meta-analysis of these data was performed using the Ingenuity Pathway Analysis (IPA) software. SOD1 plasmatic concentrations in symptomatic infected individuals (ATLL and HAM/TSP), asymptomatic carriers, and uninfected healthy subjects were evaluated by enzyme-linked immunosorbent assay ELISA Cu/Zn-SOD. MT2 and MT4 T lymphocytes were used in the in vitro assays to evaluate the basal cytoplasmatic concentration of SOD1 by Cu/Zn-SOD ELISA; and also, for evaluation of SOD1 inhibition using DETC. The DETC apoptotic capacity and the validation of its action using the antioxidant N-acetylcysteine (NAC) were evaluated by flow cytometry and quantified by staining the cells with Hoechst 33432. RESULTS AND DISCUSSION: In the chronic and acute clinical forms of ATLL, we have observed that the NFE2L2 gene, related to the antioxidant response regulation, is being differentially expressed, under positive regulation, and that the classical lymphocyte proliferation pathway is activated.
SOD1 plasmatic quantifications in healthy donors (28.3, 15.6-37.75 ng/mL, n = 20), asymptomatic carriers (193.6, 170.2-327.4 ng/mL, n = 19), HAM/TSP patients (38.1, 10.6-59.25 ng/mL, n = 14) and ATLL patients (270.6, 141.8-456.9 ng/mL, n = 25) demonstrated that SOD1 concentration is significantly lower (p <0.0001) in HAM/TSP individuals, compared to asymptomatic carriers and ATLL patients, which may explain the therapeutic success of antioxidants, such as vitamin C, used in this clinical form; SOD1 concentration is also significantly higher (p <0.0001) in asymptomatic carriers compared to HAM/TSP and healthy donors, which could suggest SOD1 as a prognostic marker for ATLL; and significantly higher (p <0.0001) in ATLL patients, when compared to HAM/TSP and healthy donor patients, which may represent a promising therapeutic target for the treatment of this pathology. It was also possible to demonstrate a gradual decrease of cell viability, of MT2 and MT4 lymphocytes, with the increase of DETC concentration, and a greater sensitivity, to this drug, of MT4 cells (IC50 = 11.92μM) when compared to MT2 cells (IC50 = 26.45μM). We also determined the maximum of positive response to DETC treatment that was superior in MT2 lymphocytes (50μM) compared to MT4 lymphocytes (10μM). The reversion of DETC action in the two type of cells using the antioxidant NAC, for validation of SOD1 inhibition by DETC, was more prominent in MT2 (Up to 500μM DETC) than in MT4 lymphocytes (Up to 10μM DETC). These results are corroborated by the fact that MT2 lymphocytes have higher SOD1 basal cytoplasmatic concentration (6.73, 4.47–10.43 ng/mL) than MT4 lymphocytes (3.15, 2.78–3.5 ng/mL). CONCLUSION: SOD1 could be suggested as a potential therapeutic target for ATLL, as well as the use of DETC as a promising pro-oxidant therapy in this pathology.

MEMBROS DA BANCA:
Presidente - 1854449 - ALINE CRISTINA ANDRADE MOTA MIRANDA MASCARENHAS
Externo à Instituição - ANDREA THOMPSON DA POIAN - UFRJ
Externo à Instituição - LUCIANE AMORIM SANTOS - Fiocruz-Ba