UNSTABLE EXPRESSION OF THE MULTI-DRUG-RESISTANT PHENOTYPE IN CHINESE-HAMSTER OVARY CELLS RESISTANT TO OKADAIC ACID

A Chinese hamster ovary cell line resistant to okadaic acid (OA), OAR2 -3 has a mutation of the protein phosphatase (PP) 2A alpha gene and ex presses a multi-drug resistance (MDR) phenotype. In the present work, we isolated two additional OA-resistant variants, also showing MDR wit h a cross-resistance profile similar to that of OAR2-3, and with incre ased and decreased expressions of the P-glycoprotein (Pgp) and DNA top oisomerase (topo) II protein, respectively. Unlike OAR2-3, however, th ey had no mutation in the same region of the PP2A alpha gene. Except f or OA-resistance in OAR23, the MDR was found to decrease in the absenc e of OA, and this decrease was again associated with changes in topo I I- and Pgp-expressions. Thus, we conclude that 1) OA regulates the exp ressions of Pgp and topo II positively and negatively, respectively, r esulting in reversible expression of MDR irrespective of genetic chang es and 2) in OAR2-3, the mutation in the PP2A alpha gene confers stabl e resistance to OA. The MDR was also linked with collateral sensitivit y to some drugs, like cisplatin and nitrogen mustard. (C) 1997 Academi c Press.