RESUMO
Tumor cells present a known metabolic reprogramming, which makes them more susceptible for a selective cellular death by modifying its mitochondrial bioenergetics. Anticancer action of the antioxidant 9,10-dihydroxy-4,4-dimethyl-5,8-dihydroanthracen-1(4H)-one (HQ) on mouse mammary adenocarcinoma TA3, and its multiresistant variant TA3-MTXR, were evaluated. HQ decreased the viability of both tumor cells, affecting slightly mammary epithelial cells. This hydroquinone blocked the electron flow through the NADH dehydrogenase (Complex I), leading to ADP-stimulated oxygen consumption inhibition, transmembrane potential dissipation and cellular ATP level decrease, without increasing ROS production. Duroquinol, an electron donor at CoQ level, reversed the decrease of cell viability induced by HQ. Additionally, HQ selectively induced G2/M-phase arrest. Taken together, our results suggest that the bioenergetic dysfunction provoked by HQ is implicated in its anticancer action.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Hidroquinonas/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Metabolismo Energético/fisiologia , Pontos de Checagem da Fase G2 do Ciclo Celular/fisiologia , Hidroquinonas/química , Hidroquinonas/uso terapêutico , Masculino , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Mitocôndrias/fisiologiaRESUMO
13-epi-sclareol is a labdane-type diterpene isolated from the resinous exudates of the medicinal plant species Pseudognaphalium cheiranthifolium (Lam.) Hilliard et Burtt. and P. heterotrichium (Phil.) A. Anderb. This compound has antibacterial activity only against Gram-positive bacteria, showing a bactericidal and lytic action. The interaction of 13- epi-sclareol with the bacterial respiratory chain was analyzed. The compound inhibited oxygen consumption of intact Gram-positive cells, but not with Gram-negative bacteria. The compound inhibited NADH oxidase and cytochrome c reductase activities, while coenzyme Q reductase and the cytochrome c oxidase activities were not affected. These results suggest that the target site of 13-epi-sclareol is located between coenzyme Q and cytochrome c. Using cytoplasmic membrane fractions, the results of the analysis of the enzyme activities associated with the respiratory chain complexes were the same for both Gram-positive and Gram-negative bacteria, indicating that the compound has no access to the cytoplasmic membrane of intact Gram-negative bacteria. Thus, the Gram-negative envelope may act as a physical barrier that prevents the access of this compound to the site of action.