Inhibition of NAD(P)H:quinone oxidoreductase1 in ethacrynic acid-resistant human colon carcinoma cells.
Human colon carcinoma HT29 cells sensitive (WT) and resistant (HT/M and HT/S) to ethacrynic acid (EA) were used to investigate the role of NAD(P)H:quinone oxidoreductase1 (NQO1) in drug resistance. Significant decreases in the levels of NQO1 activity were observed in resistant cells as compared with the sensitive cells. However, the decreased activities of NQO1 in resistant cells were found to be due to inhibition of the enzyme by EA. Human NQO1 cDNA-derived protein in monkey kidney COS1 cell extract was used to demonstrate that in vitro inhibition of NQO1 activity by EA was rapid, reversible and concentration dependent, with an IC50 value of 250 microM. These results suggest that NQO1 may not have a role in EA resistance of human colon carcinoma HT29 cells and that EA is an inhibitor of NQO1 activity.
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111.
P
P
Joseph
M C
MC
Sharma
A K
AK
Jaiswal
D000818:Animals; D003110:Colonic Neoplasms / Q000201:enzymology*; D018076:DNA, Complementary / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004976:Ethacrynic Acid / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D007668:Kidney / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D016660:NAD(P)H Dehydrogenase (Quinone); D004976:Ethacrynic Acid