Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible?
BACKGROUND
It is generally accepted that P-glycoprotein 170 (MDR1/Pgp170) expression in breast tumors results in poor response to chemotherapy due to its ability to export chemotherapeutic agents. Studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may enhance the anti-tumor activity of cancer chemotherapeutic agents and reduce the risk of many cancers. The best known function of NSAIDs is to block the enzyme cyclooxygenase (Cox), the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. In this study we investigated whether expression of the inducible isoform of Cox (Cox-2) is linked with the multidrug resistance phenotype in breast cancer.


METHODS
Expression of Cox-2 and MDR1/Pgp170 was investigated in tumor specimens along with normal epithelium in breast cancer patients using immunohistochemisrty. Expression of Cox-2, MDR1/Pgp170, Protein Kinase C (PKC), and Activator Protein 1 (AP1) were investigated in a series of increasingly resistant human MCF-7 breast cancer cells compared to wild type using immunohistochemistry, Western blots, Northern blots, RT-PCR, and Southern blots.


RESULTS
Immunohistochemical analyses of human breast tumor specimens revealed a strong correlation between expression of Cox-2 and MDR1/Pgp170. In drug resistant cell lines that over-express MDR1/Pgp170 there was also significant up-regulation of Cox-2 expression. In addition, PKC and AP1 subunits c-Jun and c-Fos were also upregulated. We hypothesized that increased prostaglandin production by Cox-2 induces PKC and the expression of transcriptional factor c-Jun, which in turn, induces the expression of MDR1/Pgp170.


CONCLUSIONS
We propose that pretreatment with selective Cox-2 inhibitors may be useful in the prevention of multidrug resistance in response to cancer chemotherapy and should be further evaluated.
Ratnasinghe
D
D
Cancer Prevention Studies Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD 20892-7058, USA. DR132K@NIH.gov
Daschner
P J
PJ
Anver
M R
MR
Kasprzak
B H
BH
Taylor
P R
PR
Yeh
G C
GC
Tangrea
J A
JA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004790:Enzyme Induction; D018628:Gene Dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D016612:Paraffin Embedding; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011493:Protein Kinase C / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007527:Isoenzymes; D008565:Membrane Proteins; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D015232:Dinoprostone