Inhibition of P-glycoprotein activity and chemosensitization of multidrug-resistant ovarian carcinoma 2780AD cells by hexanoylglucosylceramide.
In the present study we show that neutral hexanoyl-(glyco)sphingolipids inhibit P-glycoprotein (Pgp) activity in human ovarian 2780AD cells. By contrast, hexanoylceramide and the gangliosides GM(3) and GM(2) had no effect on Pgp activity, whereas sphingosine had a stimulating effect. In the case of hexanoylglucosylceramide, inhibition of Pgp activity by was reflected by a regained doxorubicin sensitivity of cells, which were grown in medium supplemented with the lipid. Our results lead to the conclusion that a direct transmodulation of Pgp activity by glycolipids occurs, depending on lipid headgroup structure, which can result in reduced resistance to the chemotherapeutic agent doxorubicin.
Veldman
R J
RJ
Groningen Institute of Drug Studies, Department of Physiological Chemistry, University of Groningen, A. Deusinglaan 1, AV Groningen, 9713, The Netherlands.
Sietsma
H
H
Klappe
K
K
Hoekstra
D
D
Kok
J W
JW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D005963:Glucosylceramides / Q000494:pharmacology*; D006801:Humans; D010051:Ovarian Neoplasms; D020112:Rhodamine 123 / Q000378:metabolism; D013107:Sphingolipids / Q000494:pharmacology*; D013110:Sphingosine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005963:Glucosylceramides; D013107:Sphingolipids; D020112:Rhodamine 123; D004317:Doxorubicin; D013110:Sphingosine