Synthesis and protective effects of coumarin derivatives against oxidative stress induced by doxorubicin.

The use of doxorubicin (DOX) in the treatment of solid tumors is limited by cardiotoxicity essentially due to oxidative stress generation. The aim of this study was to identify coumarin derivatives displaying a protective antioxidant activity without affecting DOX antitumoral efficiency. A set of eighteen coumarinic derivatives was synthesized. Their antioxidant power was evaluated in vitro with the FRAP (ferric reducing ability of plasma) method and in human breast adenocarcinoma MCF7 cells using H(2)DCFDA (2',7'-dichlorodihydrofluorescein diacetate) in a cytometric analysis. 4-Methyl-7,8-dihydroxycoumarin was found to exhibit an important antioxidant strength, a low cytotoxicity, and could decrease ROS (reactive oxygen species) production generated by DOX treatment without affecting DOX cytotoxicity in MCF7 cells.

Protection of CDC25 phosphatases against oxidative stress in breast cancer cells: evaluation of the implication of the thioredoxin system.

Reactive oxygen species regulate protein functionality. Cell cycle CDC25 phosphatases are targets of such oxidative regulation in vitro. We sought to evaluate if a thioredoxin (trx)-dependent redox regulation of CDC25 exists in cancer cells. For that purpose, we used MCF7 and MDA-MB 231 breast cancer cells, which express trx1 differentially, together with two trx/thioredoxin reductase (trxR) inhibitors, Auranofin and Acrolein. Auranofin could induce a full trxR inhibition associated with ROS production in both cell lines. Acrolein could provoke similar effects only in MDA-MB 231 cells with a low trx1 expression. Simultaneous trx1 oxidation and trxR inactivation occurred only in the presence of Acrolein and resulted in a G2-M cell cycle arrest, without full CDC25 inhibition in MDA-MB 231 cells. Our data suggest that the maintenance of CDC25 activity does not fully rely on the trx system in breast cancer cells, even in the presence of a major oxidative stress.