Full text
| |
| Author(s): |
Thais Petrochelli Banzato
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2018-08-31 |
| Examining board members: |
João Ernesto de Carvalho;
Bruno Bueno Silva;
Rejane Maira Góes;
Giovanna Barbarini Longato;
Patricia da Silva Melo
|
| Advisor: | João Ernesto de Carvalho; Débora Barbosa Vendramini Costa |
| Abstract | |
The tumor microenvironment offers multiple targets for anticancer therapy and the co-treatment with drugs that modify this environment may provide an adjuvant response to chemotherapies with specific targets. Brazilian Red Propolis presents a unique chemical composition enriched in isoflavonoids and the combination between anticancer drugs and extracts or compounds derived from red propolis could offer a significant and effective advantage in the sensitization of monotherapy, overcoming drug-induced resistance in cancer patients. The objective of this study was to evaluate the antitumor effects of the Ethanolic Extract of Red Propolis (EERP) in vitro and in vivo, together with its anti-inflammatory activity and evaluation of mechanisms of cell death. The in vitro antiproliferative activity was evaluated in different human cancer cell lines and the in vitro mechanisms of action were further explored in the PC-3 line (human prostatic adenocarcinoma). In vivo antitumor activity was analyzed by the Ehrlich solid tumor model in male Balb / C mice, orally treated with EERP (50, 100 and 200 mg / kg) and in transgenic adenocarcinoma of the prostate (TRAMP) mice who were treated with EERP (50 mg / kg) five times a week for 30 days (8 to 12 weeks of age). The anti-inflammatory activity was evaluated through carrageenan-induced paw edema and through different agents (compound 48/80, bradykinin, prostaglandin E2) in male Balb / C mice. Neutrophil activation was assessed by myeloperoxidase activity in croton oil-induced ear edema. For Bioassay-guided fractionation, EERP has gone through different fractionation and purification methods (liquid-liquid partition, dry column, C18 open column, preparative HPLC, analytical HPLC and RMN), and the fractions obtained at each step were evaluated in vitro for antiproliferative activity in cancer cell lines. EERP promoted growth inhibition and cytotoxicity in a concentration-dependent way, without selectivity for a tumor type, indicating that its effects are directed to a tumor process common among all tumor cells tested. The investigation of the mechanism of action in prostate cell line (PC-3) revealed that the EERP inhibited cell proliferation, inducing cell cycle arrest in the G1 phase and inducing cell death by a combination of apoptosis and necroptosis. EERP was able to decrease Ehrlich solid tumor growth in the three doses tested, and in TRAMP animals, EERP treatment delayed the prostatic adenocarcinoma progression, reduced epithelial cells proliferation, induced apoptosis, and decreased COX-2 expression. In the inflammation models, EERP showed dose-dependent activity in the carrageenan-induced paw edema, with the highest dose (200 mg/kg) inhibiting the formation of edema within the first hours until the end of the experiment. Pre-treatment with EERP (200 mg/kg) significantly inhibited paw edema formation induced by compound 48/80, bradykinin and PGE2, illustrating their effects on vasoactive mediators. Moreover, the inhibition of neutrophil activation was confirmed using the croton oil-induced ear edema in mice. Finally, through the evaluation of physicochemical and spectrometric data of this study it was possible for the isolation and structural determination of an unpublished molecule, which will be described for the first time in the literature. Thus, the combined antitumoral and anti-inflammatory activities suggest that EERP targets multiple hallmarks of cancer, directly affecting tumor cell proliferation and the tumor environment, modulating tumorigenesis possibly through the reduction of tumor-associated inflammation (AU) | |
| FAPESP's process: | 13/24416-1 - Anticancer and anti-inflammatory activity of red propolis and its bioactive compounds. |
| Grantee: | Thais Petrochelli Banzato |
| Support Opportunities: | Scholarships in Brazil - Doctorate |