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
✍ Scribed by Pavel G. Komarov; Alexander A. Shtil; Lela E. Buckingham; M. Balasubramanian; Olga Piraner; R. Martin Emanuele; Igor B. Roninson; John S. Coon
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- French
- Weight
- 734 KB
- Volume
- 68
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Fatty acid ester surfactants Cremophor EL and Solutol H S I 5 were described earlier as modulators of multidrug resistance mediated by MDR I P-glycoprotein (Pgp). We have shown that the most active components of these polydisperse surfactants are fatty acid-polyethylene glycol-fatty acid diesters (FA-PEG-FA). A new generation of Pgp-surfactant inhibitors of defined structure was therefore synthesized. In the present study we show that these compounds are also able to inhibit upregulation of MDRI gene expression caused by cytarabine (AM-C) and doxorubicin in human tumor cell lines H9 and KB 3-I, which express minimal levels of MDR I mRNA. The surfactant inhibitors, however, had no effect on the induction of MDR I gene expression by protein kinase C agonists. Using a set of FA-PEG-FA diesters with various fatty acids and different lengths of the PEG domain, we demonstrated that the activity of diester preparations as inhibitors of drug-induced MDRI activation was in proportion to their activity as inhibitors of Pgp function. Oleic and stearic acid diesters with PEG 900 (20 ethylene oxide units) were the most potent. The poloxamer analogs of these diesters demonstrated similar effects. In contrast, the well-known, structurally unrelated inhibitors of Pgp activity, verapamil, cyclosporin A and PSC 833, had no inhibitory effect on drug-induced MDRI activation. The ability of FA-PEG-FA diesters to inhibit both Pgp function and druginduced MDR I activation suggests that these chemomodulators may be uniquely useful for the prophylaxis of Pgp-mediated multidrug resistance in drug-treated tumors.