Physiological Stress-Induced Drug Resistance and Its Reversal
Annual rept. 1 Jul 99-30 Jun 2000
GEORGE WASHINGTON UNIV WASHINGTON DC
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Physiological stress conditions associated with solid tumors play a role in chemotherapeutic resistance. Treatment with hypoxia or chemical stress agents causes EMT6 mouse mammary tumor cells to develop resistance to teniposide and etoposide, a topoisomerase II inhibitor. We have shown that prostaglandin A1 can fully reverse stress-induced resistance to teniposide or etoposide and the PGA1 can reverse this resistance when given either prior to or after the stress. PGA1 could also block activation of the transcription factor, NF-kB, as measured by gel shift assays or a luciferase reporter gene. To test whether NF-kB was directly involved in stress-induced resistance, an inducible promoter plasmid system containing a mutant IkB gene which was non- phosphorylatable was introduced into EMT6 cells as a dominant negative mutant. Expression of the dominant negative mutant prevented the stress activation of NE-kB and reverted the resistant phenotype to a drug sensitive phenotype. These results imply that NE-kE directly mediates both chemical and physiological stress-induced drug resistance in cancer cells and suggest that agents like PGA1 which prevent NP-kB activation may improve the efficacy of topoisomerase II inhibitors.
- Medicine and Medical Research
- Stress Physiology