Banca de DEFESA: JESSICA MARTINS DE MOURA VALADARES

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : JESSICA MARTINS DE MOURA VALADARES
DATE: 28/09/2021
TIME: 09:00
LOCAL: Videoconferência
TITLE:

Cytotoxic mechanism of digitoxin monosaccharide analogues through modulation of cellular oxidative stress and alteration of calcium 

KEY WORDS:

Digitoxin, Cardiotonic Steroids, PMCA, Cancer.

PAGES: 61
BIG AREA: Ciências da Saúde
AREA: Farmácia
SUMMARY:

Cancer is a leading cause of death worldwide and its treatment is hampered by the lack of specificity and side effects of current drugs. Thus, the search for new antitumor agents and targets becomes important to find a tumor cell selective drug. In this context, cardiotonic steroids (CTS), such as digitoxin, are compounds that interact with Na, K-ATPase to induce antineoplastic effects, however these digitalis have a narrow therapeutic index. Thus, the synthesis of analogs with modifications in digitoxin glycosidic moiety has been shown to be an interesting approach for more selective and more effective analogs as antitumor agents. In addition, CTS may induce apoptosis in tumor cells by interfering with mitochondrial function, inducing oxidative stress and cell death. Therefore, the aim of this study was to evaluate the antitumor mechanism of the α-L-amicetosis digitoxigenin and α-L-rhamnose digitoxigenin compounds with respect to oxidative parameters in HeLa cells and to evaluate the involvement of PMCA4 in the antitumor mechanism of these analogs. For this, the levels of hydrogen peroxide (H2O2), reduced glutathione (GSH) catalase activity (CAT) and superoxide dismutase (SOD) were measured and the analogues induced a state of oxidative stress increasing the levels of H2O2 and reducing the levels of GSH and SOD activity. Involvement of PMCA4, an important enzyme for the control of intracellular Ca2+ levels, was evaluated using HT-29 cells treated with the analogs for 24 and 48 hours. Briefly, HT-29 cells before reaching confluence do not express PMCA4 and the analogs were very cytotoxic under this condition. In addition, α-L-rhamnose digitoxigenin increased NCS-1 and AIF levels which may be a reason for its higher cytotoxicity. However, after 5 days of confluence where cells express PMCA4 on the plasma membrane the analogs were not cytotoxic. This suggests that the analogs induce increased intracellular Ca2+ levels because the presence or absence of PMCA4 in the plasma membrane is important for this cytotoxicity. Therefore our results promoted a better understanding of the mechanism of action of these analogs and highlighted PMCA4 as an important target for the development of antitumor agents.

BANKING MEMBERS:
Presidente - 1526269 - LEANDRO AUGUSTO DE OLIVEIRA BARBOSA
Interno - 1422156 - FERNANDO DE PILLA VAROTTI
Externa ao Programa - 1106384 - LUCIANA ESTEFANI DRUMOND DE CARVALHO
Externo à Instituição - MARCO TULIO CORREA PESSOA
Externo à Instituição - JÚLIO ALBERTO MIGNACO - UFRJ