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| Author(s): |
Larissa Shiozawa Turri
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba |
| Defense date: | 2018-02-22 |
| Examining board members: |
João Ernesto de Carvalho;
Carmen Silvia Passos Lima;
Fernanda Klein Marcondes;
Giovanna Barbarini Longato;
Maria Jose Queiroz de Freitas Alves
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| Advisor: | Ana Lucia Tasca Gois Ruiz; Mary Ann Foglio; João Ernesto de Carvalho |
| Abstract | |
Currently around 75% of anticancer drugs are derived from natural products, showing the great potential of these products in new drug research and development for the treatment of this set of diseases. Previous studies carried out at the Center for Chemical, Biological and Agricultural Research (CPQBA - Unicamp) revealed that extracts and active ingredients obtained from "Psidium guajava" L. show potential anticancer action both in human tumor cell culture and in experimental models with laboratory animals. Intraperitoneal treatment with the enriched fraction (Guajadial and Psidial A) of the species resulted in inhibition of the growth of Ehrlich solid tumors at all doses (10, 30 and 50 mg/kg). The significant increase in the weight and size of the uteri of the animals treated with the fraction suggested a possible hormonal action of the active principles, which was then evaluated using the in silico molecular docking technique. Both Guajadial and Psidial A showed significant affinity for both isoforms of estrogen receptors (ER-"alfa" and ER-"beta"), thus indicating a possible action on hormone receptors. In this context, this work evaluated, both in vitro and in vivo, the antiproliferative activity and estrogenic/antiestrogenic action of the crude extract and fractions obtained from "P. guajava" L. leaves. By chromatographic techniques fractions were obtained, some active ones including FB1c and FFINAL that showed antiproliferative activity in vitro with selectivity for human tumor cell lines MCF-7 and MCF-7 BUS (TGI = 5, 59 and 2.27 mg / mL, respectively), thus demonstrating a possible correlation between the antiproliferative activity and hormone action. This correlation was confirmed in both the E-screen tests for in vivo tests that assess uterotrophic activity, which found that the FFINAL was able to block the proliferative effect of estradiol on the MCF-7 cells BUS and uterus rats pre-pubescent. The anticancer activity was confirmed by in vivo Ehrlich's solid tumor model and by Hollow fiber assay, after oral treatment. The tests that evaluate the mechanisms of cell death, by flow cytometry showed that fractions FB1c (5 and 10 ug / ml) and FFINAL (2.5 ug / ml) after 24 hours of treatment, were able to induce externalization of phosphatidylserine residues in the cytoplasmic membranes of MCF-7 and MCF-7 cells BUS, suggesting, therefore, death by apoptosis. Compared to the action of tamoxifen on the cell cycle, treatment with FFINAL of MCF-7 BUS cells caused cell cycle arrest in the G1 phase of the cycle, at all time periods evaluated (24, 30 and 48 hours). Finally, the test chemical carcinogenesis induced by compound 1-methyl-1-nitrosourea (MNU), demonstrated that the induction of breast tumors was not effective with low index tumors 120 days after carcinogen administration (AU) | |
| FAPESP's process: | 14/01283-9 - Mechanism of anticancer activity and its relation to hormonal activity of extracts and fractions obtained from the leaves of Psidium guajava L. |
| Grantee: | Larissa Shiozawa |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |