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| Author(s): |
Gabriela Menezes Marchetti
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2012-08-31 |
| Examining board members: |
João Ernesto de Carvalho;
Durvanei Augusto Maria;
Patricia da Luz Moreira;
Cristina Pontes Vicente;
Carina Denny
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| Advisor: | Mary Ann Foglio; João Ernesto de Carvalho |
| Abstract | |
Plants have provided a large number of new substances and many drugs have based for the synthesis of them. The dichloromethane crude extract presented antiproliferative activity inhuman tumor cell culture and in vivo antitumor activity against ascitic and solid Ehrlich tumor models. The results obtained with Calea pinnatifida, species from Asteraceae family,may result in the development of new chemotherapeutic agents by the presence of germacranolides (sesquiterpene lactones) in their chemical composition. The arucanolide was obtained by the fractionation of crude dichloromethane extract after the precipitation of chlorophyll and graxes using a lead acetate basic solution. Arucanolide shows antiproliferative activity in vitro against human tumor cells lines with selectivity for melanoma and kidney. It was proved that the arucanolide is capable of inducing apoptosis,by the intrinsic pathway, through caspase avtivation, generating free radicals in U-118 MG glioblastoma and SK-MEL-2 melanoma cells. At the adenocarcinoma of cervix cells HeLa the mechanism by which arucanolide acts may be different, because the intrinsic pathway seems to be not as important as in the others cells, suggesting the involvement of the extrinsic pathway of apoptosis. The use of HeLa cells transfected with the gene of Bcl-xl, has not hindered the induction of apoptosis in these cells, showing the lack of importance of mitochondria in this apoptotic process, while in SK-MEL-2 Bcl-xL cells, the arucanolide treatment significantly reduced the apoptosis induction. In the B16-F10 cells, the arucanolide induces caspase-dependent apoptosis in vitro and has antitumor activity in vivo against the same cell line, in a subcutaneous melanoma model. The apoptosis induction was not detected in vivo, suggesting that arucanolide could act by preventing the tumor cell proliferation in vivo. At the model of experimental metastasis with the melanoma cell lineB16-F10 there is a tendency to reduce lung metastasis in mice treated with arucanolide, showing few signs of liver toxicity. With all this results, we conclude that the arucanolídeois able to induce apoptosis in human and murine tumor cells lines, and its death pathway, depends on the cell type evaluated. This compound may act by intrinsic or extrinsic apoptosis pathways. The arucanolide also reduces tumor growth in vivo and it is a promising new chemotherapic for clinical research (AU) | |