Oxidative stress-mediated up-regulation of ABC transporters in lung cancer cells.

ABSTRACT

This paper aimed to evaluate the role of oxidative stress in the regulation of ABC transporters in human lung cancer (A549) cells facing substrate (doxorubicin, DOX) and nonsubstrate (ethanol, ETH and hydrogen peroxide, HP) chemicals. After 24-h treatment, all the chemicals caused significant cytotoxicity as reflected by the reduction in cell viability and the increase in reactive oxygen species (ROS) levels. Depending on the rescuing effects of ROS scavenger including glutathione (GSH) and Vitamin C, the toxicity dependence on oxidative stress were found to be HP > ETH > DOX. The addition of transporter inhibitors significantly enhanced the ROS levels and death-inducing effects of chemicals, indicating the universal detoxification function of ABC transporters. At moderate ROS levels (about 3-4-folds of control levels, caused by 10 µM DOX, 400 mM ETH, and 400 µM HP), all the three chemicals induced the gene expressions and activities of ABC transporters, but these values decreased at too high ROS levels (8.36-folds of control levels) caused by HP at LC50 (800 µM). Such induction could be attenuated by GSH and KCZ, and was completely abolished by 50 µM KCZ, indicating an important role of oxidative stress and pregnane X receptor (PXR) in the induction of ABC transporters. Finally, this paper revealed the critical role of oxidative stress in the modulation of ABC transporters by either substrate or nonsubstrate chemicals during 24-h treatment. Such information should be beneficial for overcoming ABC transporter-mediated multidrug resistance.