Participação das vias atm/atr e c-myc/gsh nos efeitos antitumorais da cordiaquinona J induzidos pelo estresse oxidativo

Abstract

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.