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

Publication ,  Journal Article
Brandes, LM; Lin, ZP; Patierno, SR; Kennedy, KA
Published in: Mol Pharmacol
September 2001

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.

Duke Scholars

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

September 2001

Volume

60

Issue

3

Start / End Page

559 / 567

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Phosphorylation
  • Pharmacology & Pharmacy
  • Oxygen
  • Okadaic Acid
  • NF-kappa B
  • NF-KappaB Inhibitor alpha
  • Mutation
  • Mice
  • I-kappa B Proteins
 

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

September 2001

Volume

60

Issue

3

Start / End Page

559 / 567

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Phosphorylation
  • Pharmacology & Pharmacy
  • Oxygen
  • Okadaic Acid
  • NF-kappa B
  • NF-KappaB Inhibitor alpha
  • Mutation
  • Mice
  • I-kappa B Proteins