Reversal of physiological stress-induced resistance to topoisomerase II inhibitors using an inducible phosphorylation site-deficient mutant of I kappa B alpha.

Abstract

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-kappa B. Pretreatment with the proteasome inhibitor carbobenzyoxyl-leucinyl-leucinyl-leucinal inhibits stress-induced NF-kappa B activation and reverses BFA-induced drug resistance. To test whether NF-kappa B specifically mediates stress-induced drug resistance, an inducible phosphorylation site-deficient mutant of I kappa B alpha (I kappa B alpha M, S32/36A) was introduced into EMT6 cells. In this study, we show that I kappa B alpha M expression inhibits stress-induced NF-kappa B activation and prevents BFA-, hypoxia-, and OA-induced resistance to etoposide. These results indicate that NF-kappa B activation mediates both chemical and physiological drug resistance to etoposide. Furthermore, they imply that coadministration of agents that inhibit NF-kappa B may enhance the efficacy of topoisomerase II inhibitors in clinical cancer chemotherapy.

• Authors: L M Brandes, Z P Lin, S R Patierno, K A Kennedy
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 60 Issue 3 Pg. 559-67 (Sep 2001) ISSN: 0026-895X [Print] United States
• PMID: 11502888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• DNA-Binding Proteins
• I-kappa B Proteins
• NF-kappa B
• Nfkbia protein, mouse
• NF-KappaB Inhibitor alpha
• Okadaic Acid
• Brefeldin A
• Etoposide
• Oxygen

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Brefeldin A (pharmacology)
• Cell Hypoxia
• Cell Survival (drug effects)
• DNA-Binding Proteins (biosynthesis, genetics, physiology)
• Drug Interactions
• Drug Resistance, Neoplasm (genetics)
• Etoposide (pharmacology)
• I-kappa B Proteins
• Mice
• Mutation
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Okadaic Acid (pharmacology)
• Oxygen (metabolism)
• Phosphorylation
• Tumor Cells, Cultured