%0 journal article
%@ 0014-5793
%A Wartenberg, M.,Hoffmann, E.,Schwindt, H.,Gruenheck, F.,Petros, J.,Arnold, R.S.,Hescheler, J.,Sauer, H.

%D 2005
%J FEBS Letters
%N 20
%P 4541-4549 
%R doi:10.1016/j.febslet.2005.06.078
%T Reactive oxygen species-linked regulation of the multidrug resistance transporter P-glycoprotein in Nox-1 overexpressing prostate tumor spheroids
%U https://doi.org/10.1016/j.febslet.2005.06.078
20 
%X Expression of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) has been,demonstrated to be regulated by hypoxia-inducible factor-1a (HIF-1a) and inhibited by intracellular ROS. Herein, P-gp and HIF-1a expression were investigated in multicellular,prostate tumor spheroids overexpressing the reactive oxygen (ROS)-generating enzyme Nox-,1 in comparison to the mother cell line DU-145. In Nox-1-overexpressing tumor spheroids,(DU-145Nox1) generation of ROS as well as expression of Nox-1 was significantly increased as compared to DU-145 tumor spheroids. ROS generation was significantly inhibited in the presence of the NADPH-oxidase antagonists diphenylen-iodonium chloride (DPI) and 4-(2-,aminoethyl)benzenesulfonyl fluoride (AEBSF). Albeit growth kinetic of DU-145Nox1 tumor spheroids was decreased as compared to DU-145 spheroids, elevated expression of Ki-67 was observed indicating increased cell cycle activity. In DU-145Nox1 tumor spheroids expression,of HIF-1a as well as P-gp was significantly decreased as compared to DU-145 spheroids which resulted in an increased retention of the anticancer agent doxorubicin. Pretreatment with the free radical scavengers vitamin E and vitamin C increased the expression of P-gp as,well as HIF-1a in Nox-1-overexpressing cells, whereas no effect of free radical scavengers,was observed on mdr-1 mRNA expression. In summary the data of the present studydemonstrate that the development of P-gp-mediated MDR is abolished under conditions of elevated ROS levels, suggesting that the MDR phenotype can be circumvented by modest increase of intracellular ROS generation.