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Reactive oxygen species‐linked regulation of the multidrug resistance transporter P‐glycoprotein in Nox‐1 overexpressing prostate tumor spheroids
Author(s) -
Wartenberg Maria,
Hoffmann Edda,
Schwindt Heinrich,
Grünheck Frank,
Petros John,
Arnold J. Rebecca S.,
Hescheler Jürgen,
Sauer Heinrich
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.06.078
Subject(s) - reactive oxygen species , chemistry , nadph oxidase , intracellular , spheroid , microbiology and biotechnology , cancer research , biology , biochemistry , in vitro
Expression of the multidrug resistance (MDR) transporter P‐glycoprotein (P‐gp) has been demonstrated to be regulated by hypoxia‐inducible factor‐1α (HIF‐1α) and inhibited by intracellular reactive oxygen species (ROS). Herein, P‐gp and HIF‐1α expression were investigated in multicellular prostate tumor spheroids overexpressing the 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‐1α 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‐1α 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 study demonstrate 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.