Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / As cordiaquinonas sÃo naftoquinonas meroterpenÃides isolados de plantas pertencentes ao gÃnero Cordia com vÃrias atividades biolÃgicas descritas, incluindo atividades antifÃngica, larvicida e citotÃxica. O objetivo deste trabalho foi avaliar o potencial anticÃncer de uma cordiaquinona isolada das raÃzes da planta Cordia leucocephala. O presente estudo avaliou o potencial citotÃxico da cordiaquinona J em vÃrias linhagens de cÃlulas tumorais e normais pelo teste do MTT e seu possÃvel mecanismo de aÃÃo. A cordiaquinona J mostrou valores de CI50 variando de 4,6 a 6,8 μM em cÃlulas leucÃmicas e 33,6 a 37 μM em cÃlulas normais, apÃs 24 horas de incubaÃÃo. Nas cÃlulas HL-60 foi observado induÃÃo de apoptose preferencialmente pela via extrÃnseca. A induÃÃo do dano ao DNA observado pelo tratamento com a cordiaquinona J atravÃs do ensaio do cometa foi associado com a ativaÃÃo de proteÃnas quinases da via ATM/ATR. O dano ao DNA, assim como a ativaÃÃo das proteÃnas quinases da via ATM/ATR foi visualizado em cÃlulas HL-60, mas nÃo em cÃlulas normais. Estes efeitos em HL-60 podem estar relacionados com a depleÃÃo da expressÃo proteica de glutationa e de c-myc observados. O potencial anticÃncer foi confirmado in vivo atravÃs da inibiÃÃo do tumor sarcoma-180 em 72,5% apÃs o tratamento com 50 mg/kg de cordiaquinona J. O prÃ-tratamento tanto das cÃlulas quanto dos animais com N-acetil-L-cisteina inibiu todos os efeitos observados in vitro e in vivo reforÃando o papel da geraÃÃo das espÃcies reativas de oxigÃnio na atividade antitumoral da cordiaquinona J. / Cordiaquinones are meroterpenoid naphtoquinones from plants belonging to the genus Cordia with several described biological activities, including antifungal, larvicidal and cytotoxic effects. The aim of this study was to evaluate the anticancer potential of a cordiaquinone isolated from the roots of Cordia leucocephala plant. The present study evaluated the cytotoxic potential of cordiaquinone J in several tumor and normal cell lines by MTT assay and its possible mechanism of action. The study of the mechanism of action of cordiaquinones L and M, in human leukemia cells (HL-60) showed induction of cell death by apoptosis, and these effects were related to the induction of oxidative stress. Then the study was continued only with the cordiaquinone J. The cordiaquinone J showed IC50 values ranging from 4.6 to 6.8μM in leukemia cells and 33.6 to 37 μM in normal cells, after 24 hours of incubation. In HL-60 cells was observed apoptosis induction preferentially by extrinsic pathway. The induction of DNA damage by cordiaquinone J observed by comet assay was associated with activation of protein kinases of ATM/ATR pathway. The DNA damage, as well as activation of protein kinases via the ATM / ATR was observed in HL-60 cells but not in normal cells. These effects in HL-60 cells may be related to the depletion of protein expression of glutathione and c-myc observed. The anticancer potential was confirmed in vivo through inhibition of sarcoma-180 tumor by 72.5% after the treatment with 50 mg/kg of cordiaquinone J. The pre-treatment of cells or animals with N-acetyl-L-cysteine abolished most of the in vitro and in vivo observed effects, reinforcing the role of reactive oxygen species generation in cordiaquinone J activity.
| Identifer | oai:union.ndltd.org:IBICT/oai:www.teses.ufc.br:6075 |
| Date | 29 October 2012 |
| Creators | Josà Delano Barreto Marinho Filho |
| Contributors | LetÃcia Veras Costa-Lotufo, Geanne Matos de Andrade, Marcellus Henrique Loiola Ponte de Souza, GardÃnia Carmen Gadelha MilitÃo, JoÃo Ernesto de Carvalho |
| Publisher | Universidade Federal do CearÃ, Programa de PÃs-GraduaÃÃo em Farmacologia, UFC, BR |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFC, instname:Universidade Federal do Ceará, instacron:UFC |
| Rights | info:eu-repo/semantics/openAccess |
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