TY - JOUR T1 - Reversal of Physiological Stress-Induced Resistance to Topoisomerase II Inhibitors Using an Inducible Phosphorylation Site-Deficient Mutant of IκBα JF - Molecular Pharmacology JO - Mol Pharmacol SP - 559 LP - 567 VL - 60 IS - 3 AU - Lori M. Brandes AU - Z. Ping Lin AU - Steven R. Patierno AU - Katherine A. Kennedy Y1 - 2001/09/01 UR - http://molpharm.aspetjournals.org/content/60/3/559.abstract N2 - Physiological stress conditions associated with the tumor microenvironment play a role in resistance to anticancer therapy. In this study, treatment of EMT6 mouse mammary tumor cells with hypoxia or the chemical stress agents brefeldin A (BFA) or okadaic acid (OA) causes the development of resistance to the topoisomerase II inhibitor etoposide. The mechanism of physiological stress-induced drug resistance may involve the activation of stress-responsive proteins and transcription factors. Our previous work shows that treatment with BFA or OA causes activation of the nuclear transcription factor NF-κB. Pretreatment with the proteasome inhibitor carbobenzyoxyl-leucinyl-leucinyl-leucinal inhibits stress-induced NF-κB activation and reverses BFA-induced drug resistance. To test whether NF-κB specifically mediates stress-induced drug resistance, an inducible phosphorylation site-deficient mutant of IκBα (IκBαM, S32/36A) was introduced into EMT6 cells. In this study, we show that IκBαM expression inhibits stress-induced NF-κB activation and prevents BFA-, hypoxia-, and OA-induced resistance to etoposide. These results indicate that NF-κB activation mediates both chemical and physiological drug resistance to etoposide. Furthermore, they imply that coadministration of agents that inhibit NF-κB may enhance the efficacy of topoisomerase II inhibitors in clinical cancer chemotherapy. The American Society for Pharmacology and Experimental Therapeutics ER -