Banca de QUALIFICAÇÃO: KIMBERLY BRITO TECCHIO

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : KIMBERLY BRITO TECCHIO
DATE: 31/03/2021
TIME: 13:30
LOCAL: Videoconferência
TITLE:

EVALUATION OF ANTITUMORAL POTENTIAL AND CHARACTERIZATION OF THE MECHANISMS OF ACTION OF β-CARBOLINK ALKALOIDS SYNTHETICS IN HUMAN CELL LINES

KEY WORDS:

Genetics; toxicology; mutagenesis; tumor.

PAGES: 64
BIG AREA: Ciências da Saúde
AREA: Farmácia
SUMMARY:

β-carbolinic alkaloids are pharmacologically active compounds, widely distributed in the environment. According to the literature, they have already been shown to be effective in the treatment of several diseases, including cancer. Therefore, in the search for new antitumor agents, the present study aimed to evaluate the cytotoxicity of twelve different synthetic βcarbolinic alkaloids and, also, to evaluate the in vitro genotoxic and mutagenic potentials of two of the most promising of these alkaloids, called NQBio-006 and NQBio- 021, using the tumor cell lines TOV-21G (ovary) and MDA-MB-231 (breast). The two compounds were chosen after their cytotoxic potential screening using the MTT assay, since they displayed lower IC50 values and demonstrated promising selectivity index values in relation to the nontumor strain WI-26VA4, after 24-hour treatments. Genotoxic and Mutagenic potential were evaluated by performing the alkaline comet assay and the cytokinesis-block micronucleus assay, respectively, after 3-hour treatments. Methyl methanesulfonate (MMS) was used as the positive control. For the alkaloid NQBio-006, genotoxicity and mutagenicity tests were performed at concentrations of 2.5; 1.9; 1.2 and 0.6 µM in the TOV-21G line, while for the compound NQBio-021 concentrations of 6.9 were performed; 5.2; 3.5 and 1.7 µM in the MDA-MB-231 strain. In addition, a mutagenicity test was performed on both compounds on the WI-26VA4 line to verify selectivity in the mutagenic concentrations of the tumor lines. The results showed that NQBio-006 did not induce primary DNA damage, as the comet test did not indicate genotoxicity. However, the compound was shown to be mutagenic, through the micronucleus test, at concentrations of 2.5 and 1.88 µM, indicating that the compound acts by aneugenesis mechanism (failure in chromosomal segregation). The compound NQBio-021 was genotoxic and mutagenic in all concentrations evaluated, which indicates that this compound is capable of causing clastogenesis (breaks in the DNA). However, none of them were mutagenic in WI-26VA4. In addition, to assess whether the compounds are good drug candidates, a prediction of in silico ADME (absorption, distribution, metabolism and excretion) parameters was performed. The results obtained showed that both alcaloids have antitumor potential, since they were cytotoxic and selective against the human tumor strains used and caused chromosomal changes that are related to the induction of cell death by apoptosis, according to the literature. Additionally they displayed good oral availability and high intestinal absorption. However, additional studies must be carried out in vitro and in vivo to assess the efficacy and safety of these compounds in antitumor treatments.

BANKING MEMBERS:
Presidente - 1680474 - FABIO VIEIRA DOS SANTOS
Interno - 1676127 - GUSTAVO HENRIQUE RIBEIRO VIANA
Externa à Instituição - JULIA TEIXEIRA DE OLIVEIRA