Διερεύνηση των μηχανισμών του κυτταρικού stress κατόπιν επιδράσεως χημειοθεραπευτικών παραγόντων ρυθμιστών των αντιδράσεων υπερευαισθησίας και φαρμάκων του γαστρεντερικού

Abstract

The recognition of Saccharomyces cerevisiae as an established experimental organism for the study of adaptive and protective cellular stress responses is attributed to the evolutionary conserved physiological, biochemical, cellular and molecular processes. The aim of this study was to investigate the effects of the pharmacologically modified yeast microenvironment and the actions of chemotherapeutic agents, modulators of hypersensitivity reactions and the drugs for the treatment of gastric ulcers under modified conditions, on the heat shock (HS) response. The agents were administered in yeast cultures, either chronically through to or acutely during the post-logarithmic phase of growth, prior to exposure to potentially lethal HS. The response to HS was evaluated by the determination of cell viability and occasionally of the growth potential after HS. Microenvironmental modifications were performed by chronic incubation of yeast cells with hormonal or immunomodulatory agents. The results demonstrated that chronic administration of the thyroid hormones 3 and 4 increased cell viability, in constrast to 17#-oestradiol and the immunomodulatory agents prednisolone, histamine, dimetindene and ranitidine. Regarding 4, the data obtained following incubation with cycloheximide, omeprazole, pantoprazole, amiodarone, dronedarone, C48/80, cromolyn, geldanamycin, 17-allylamine-17-dimethoxy-geldanamycin, irinotecan, suramin and doxorubicin, pointed to the involvement of de novo protein synthesis, + and Ca2+ homeostasis, hsp90 and topoisomerases #, ##, in the induction of the thermotolerant phenotype. Besides the variability observed in the chronic and acute administration of chemotherapeutic agents, modulators of hypersensitivity reactions and the drugs for the treatment of gastric ulcers, as well as amongst agents belonging to the same category, depending on the dose, duration of administration and combination of drugs; modifications with T4 influenced differentially the action of these agents on the cellular stress response. In conclusion, upon pharmacological modification, mostly via chronic incubation with thyroid hormones, alterations in the cellular stress response to drugs were of particular significance and provided data on the emergence of the resistant phenotype and the ‘behaviour’ of microorganisms during drug administration in the absence or presence of underlying disorders. In addition, although these data could not be extrapolated directly to mammals, the homology in many evolutionary conserved cellular processes between S. cereviciae and higher eukaryotes and the reliability of the experimental model in the cellular stress response research, provided preliminary information on the potential adjustment of drug action under pathological conditions and offered a lead for the re-evaluation of therapeutic interventions