Preliminary studies about novel strategies to reverse chemoresistance to adriamycin regarding glutathione metabolism, peroxisomal and extraperoxisomal hydroperoxide and valproic acid metabolic pathways

Abstract

The present work was aimed at defining novel strategies to reverse chemoresistance to anticancer drugs, especially by interfering with cellular glutathione metabolism, peroxisomal and/or extraperoxisomal hydroperoxide metabolic pathways. Preliminary results are presented about molecules we demonstrated to be capable of interfering with hydrogen peroxide metabolism in cells. Prior to describing these molecules, a short overview of glutathione and free radical metabolic pathways is presented as well as a rapid presentation of the characteristics of chemo-sensitivity and -resistance towards the anticancer drug adriamycin, with special emphasis on hydrogen peroxide metabolism. The strategies currently developed to reverse chemoresistance are further presented in subsequent sections, our own strategy to achieve inhibition of hydrogen peroxide breakdown and stimulation of peroxisomal hydrogen peroxide production is illustrated on the basis of molecular modelling studies and biochemical investigations on extraperoxisomal and peroxisomal metabolic pathways. Preliminary studies on cultured cells have been initiated. The perspective for future studies is presented as well as other possible models of chemoresistance as target for the design of hydrogen peroxide metabolism-interfering pharmacomolecules.

Sodium valproate, an anticonvulsant drug, stimulates human cytomegalovirus replication

“…Four metabolic pathways have been found: glucuronidation,/?-oxidation, co-oxidation, (co-1)-oxidation and the metabolism of valproate appears to be complex in regard to the natural fatty acids normally absorbed in man. Vamecq et al (1993) reported that the coenzyme A esters of valproic acid and related metabolites are handled by a peroxisomal/?-oxidation pathway distinct from fatty acid and bile acid/?-oxidation routes. In this way, VPA and related metabolites have the capacity to induce higher cellular hydrogen peroxide (H20~) levels because of their ability to act as substrates for H202-generating oxidases (Van den Branden & Roels, 1985).…”

Cell biological mechanisms of multidrug resistance in tumors.

“…There are a number ofcytosolic mechanisms for eliminating toxic reagents, including the enhanced activity of the pentose phosphate shunt (57) and changes in glutathione metabolism (58)(59)(60). Enzymes involved in both of these pathways are modified in some MDR cell lines.…”

“…Superoxide, hydrogen peroxide, and hydroxyl radicals are reactive oxygen species which can form in the reduction of oxygen by the anthracycline semiquinones. The Fe(Il)-doxorubicin complex is able to catalyze the oxidation of thiol by O2, promoting the oxidative destruction of macromolecular targets (13,14,16,17,(58)(59)(60).…”