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 described earlier as modulators of multidrug resistance mediated by MDR1 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 up-regulation of MDR1 gene expression caused by cytarabine (ARA-C) and doxorubicin in human tumor cell lines H9 and KB 3-1, which express minimal levels of 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 lengths of the PEG domain, we demonstrated that the activity of diester preparations as inhibitors of drug-induced MDR1 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 MDR1 activation. The ability of FA-PEG-FA diesters to inhibit both Pgp function and drug-induced MDR1 activation suggests that these chemomodulators may be uniquely useful for the prophylaxis of Pgp-mediated multidrug resistance in drug-treated tumors.
Komarov
P G
PG
Department of Pathology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612, USA.
Shtil
A A
AA
Buckingham
L E
LE
Balasubramanian
M
M
Piraner
O
O
Emanuele
R M
RM
Roninson
I B
IB
Coon
J S
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003561:Cytarabine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019450:Genes, MDR / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005227:Fatty Acids; D013501:Surface-Active Agents; D003561:Cytarabine; D011092:Polyethylene Glycols; D004317:Doxorubicin