Induction of pgp3 expression and reversion of the multidrug resistance phenotype in 9-OH-ellipticine-resistant Chinese hamster lung fibroblasts transfected with the MYC oncogene

Abstract Chinese hamster lung cells resistant to the DNA topoisomerase II inhibitor 9-OH-ellipticine (DC-3F/9-OH-E) are cross resistant to various drugs through the expression of the MDR phenotype. The myc oncogene was approximately 10-fold amplified and 20-fold overexpressed in parental DC-3F cells as compared with DC-3F/9-HO-E cells. Transfection of the resistant cells with a mouse c-myc gene did not alter the resistance to topoisomerase II inhibitors and, in cells with a low multidrug (MDR) expression, reversed this phenotype. Northern and Western blot analyses revealed an increased expression of pgp 1 in the DC-3F/9-OH-E cells, which was not modified in the myc -transfected clones. However, myc expression in these clones resulted in an increased expression of pgp3 , roughly in proportion to the level of myc expression. Transfection of the DC-3F/9-OH-E cells with the human MDR3 gene, homologous to pgp3 , also resulted in the reversion of the MDR phenotype. These results show that (1) expression of the transfected myc gene positively regulates pgp3 expression but has no effect on pgp1 ; (2) when observed, reversion of the MDR phenotype is proportional to the levels of myc and pgp3 expression; and (3) this reversion, resulting from pgp3 expression, is associated with a decreased functional activity of the pgp1 protein and might require an appropriate balance of pgp1 and pgp3 expression.