INHIBITION OF CYTARABINE-INDUCED MDR1 (P-GLYCOPROTEIN) GENE ACTIVATION IN HUMAN TUMOR-CELLS BY FATTY-ACID POLYETHYLENE-GLYCOL FATTY-ACID DIESTERS, NOVEL INHIBITORS OF P-GLYCOPROTEIN FUNCTION

Fatty acid ester surfactants Cremophor EL and Solutol HS 15 were descr ibed earlier as modulators of multidrug resistance mediated by MDR1 P- glycoprotein (Pgp). We have shown that the most active components of t hese polydisperse surfactants are fatty acid-polyethylene glycol-fatty acid diesters (FA-PEG-FA). A new generation of Pgp-surfactant inhibit ors of defined structure was therefore synthesized. In the present stu dy we show that these compounds are also able to inhibit upregulation of MDR1 gene expression caused by cytarabine (ARA-C) and doxorubicin i n human tumor cell lines H9 and KB 3-1, which express minimal levels o f MDR1 mRNA. The surfactant inhibitors, however, had no effect on the induction of MDR1 gene expression by protein kinase C agonists. Using a set of FA-PEG-FA diesters with various fatty acids and different len gths of the PEG domain, we demonstrated that the activity of diester p reparations as inhibitors of drug-induced MDR1 activation was in propo rtion to their activity as inhibitors of Pgp function. Oleic and stear ic acid diesters with PEG 900 (20 ethylene oxide units) were the most potent. The poloxamer analogs of these diesters demonstrated similar e ffects. In contrast, the well-known, structurally unrelated inhibitors of Pgp activity, verapamil, cyclosporin A and PSC 833, had no inhibit ory effect on drug-induced MDR1 activation. The ability of FA-PEG-FA d iesters to inhibit both Pgp function and drug-induced MDR1 activation suggests that these chemomodulators may be uniquely useful for the pro phylaxis of Pgp-mediated multidrug resistance in drug-treated tumors. (C) 1996 Wiley-Liss, Inc.