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| Author(s): |
Natalia Bromberg
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Química |
| Defense date: | 2005-04-03 |
| Examining board members: |
Nelson Eduardo Duran Caballero;
Carmen Veríssima Ferreira;
Maricilda Palandi de Mello;
Roberto Rittner Neto;
Renato Atilio Jorge
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| Advisor: | Nelson Eduardo Duran Caballero |
| Abstract | |
The immuno and chemotherapeutic potentials of two natural compounds, the proteic aggregated polymer of magnesium ammonium phospholinolate-palmitoleate anhydride (P-MAPA) isolated from Aspergillus oryzae and the cytotoxic violacein isolated from Chromobacterium violaceum, were evaluated in the present work. The murine renal cancer model (RENCA), the Ehrlich ascites tumor (EAT), the Lewis lung carcinoma (3LL), human and murine endothelial cells and the human myelocitic leukemia cell line (HL60) were used as experimental models. The results from in vivo experiments suggested an antitumoral activity for violacein in EAT-bearing mice treated with 0.1 and 1.0 mg kg, whereas the P-MAPA compound, administrated at 5 mg kg doses, also extended the survival of RENCA-bearing mice and 3LL tumors. A reduced number of pulmonary metastases was observed in the group of RENCA-bearing mice treated with P-MAPA after nephrectomy of the primary tumor-bearing kidney, suggesting that it may be useful in therapeutic approaches to treat the residual disease. Some aspects of the mechanisms involved in these responses were investigated by analysis of different in vivo and/or in vitro cellular and molecular parameters such as apoptosis induction, natural killer cell activity and cytokine production. The study of violacein cytotoxicity on RENCA, EAT and HL60 cell cultures indicated the induction of apoptosis as a mechanism of action. Several techniches were used to charaeterize the apoptotic process such as Feulgen reaction, determination of DNA fragmentation, evaluation of caspase activity, flow cytometry Annexin V/PI assay, evaluation of BcI-2 protein expression and changes in the mitochondrial transmembrane potential (Dy). The antitumoral potential of these metabolites, as demonstrated in this work, reinforces the possibility of their application on cancer therapeutics and in future studies of combined therapy (AU) | |