Prostaglandin A1 inhibits stress-induced NF-kappaB activation and reverses resistance to topoisomerase II inhibitors.
Stress conditions associated with solid tumors lead to the formation of heterogeneous tumor cell subpopulations and insensitivity to cancer chemotherapeutics. In this report, we show that EMT6 mouse mammary tumor cells treated with the chemical stress, brefeldin A (BFA), or the physiological stress, hypoxia, develop resistance to the topoisomerase II (topoII) inhibitors teniposide and etoposide. BFA and hypoxia treatment did not alter intracellular drug concentrations, topoll protein levels, or inhibit topoII activity. BFA and hypoxia did cause the activation of the nuclear transcription factor NF-kappaB. We demonstrate that pretreatment with the synthetic cyclopentenone prostaglandin A1 (PGA1) inhibits stress-induced NF-kappaB activation and reverses BFA- and hypoxia-induced resistance. The reversal of BFA-induced resistance can occur when PGA1 is administered either before or several hours after the induction of stress. Taken together, these data support the involvement of NF-kappaB in stress-induced drug resistance, show that pharmacologic inhibitors of NF-kappaB can disrupt the biological consequences of stress, and imply that inhibitors of NF-kappaB may be useful agents to enhance the clinical efficacy of topoII-directed chemotherapeutics.
Boller
Y C
YC
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
Brandes
L M
LM
Russell
R L
RL
Lin
Z P
ZP
Patierno
S R
SR
Kennedy
K A
KA
D000818:Animals; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011454:Prostaglandins A / Q000494:pharmacology*; D013713:Teniposide / Q000494:pharmacology; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D011454:Prostaglandins A; D059005:Topoisomerase II Inhibitors; D020126:Brefeldin A; D005047:Etoposide; D013713:Teniposide; D008156:Luciferases; C100573:prostaglandin A1