Prostaglandin A(1) inhibits stress-induced NF-kappa B activation and reverses resistance to topoisomerase II inhibitors

Stress conditions associated with solid tumors lead to the formation of het erogeneous tumor cell subpopulations and insensitivity to cancer chemothera peutics. In this report, we show that EMT6 mouse mammary tumor cells treate d with the chemical stress, brefeldin A (BFA), or the physiological stress, hypoxia, develop resistance to the topoisomerase II (topoII) inhibitors te niposide and etoposide. BFA and hypoxia treatment did not alter intracellul ar drug concentrations, topoII protein levels, or inhibit topoII activity. BFA and hypoxia did cause the activation of the nuclear transcription facto r NF-kappaB. We demonstrate that pretreatment with the synthetic cyclopente none prostaglandin A(1) (PGA(1)) inhibits stress-induced NF-kappaB activati on and reverses BFA- and hypoxia-induced resistance. The reversal of BFA-in duced resistance can occur when PGA(1) is administered either before or sev eral hours after the induction of stress. Taken together, these data suppor t the involvement of NF-kappaB in stress-induced drug resistance, show that pharmacologic inhibitors of NF-kappaB can disrupt the biological consequen ces of stress, and imply that inhibitors of NF-kappaB may be useful agents to enhance the clinical efficacy of topoII-directed chemotherapeutics.