Elevated uptake of low density lipoprotein by drug resistant human leukemic cell lines.
Overexpression of a 170kD membrane glycoprotein, P-glycoprotein (Pgp), which acts as an energy dependent efflux pump for cytotoxic drugs is believed to be one of the factors that is responsible for clinical drug resistance. Recent studies suggest that Pgp is also responsible for the intracellular transport of cholesterol from the plasma membrane to the endoplasmic reticulum. Leukemic cells from patients with acute myelogenous leukemia have an elevated uptake of low density lipoprotein (LDL) when compared with white blood cells from healthy individuals. Since elevated LDL receptor expression and multidrug resistance are both common events in leukemic cells, we investigated LDL receptor expression in sensitive and drug resistant human leukemic cell lines. We found a 2- to 10-fold higher uptake of LDL in five out of five drug resistant K562 cell lines. All three drug resistant HL60 cell lines studied also had higher uptake than the parental cells. The LDL receptor expression in vincristine resistant Pgp positive K562 cells was less sensitive to downregulation by sterols than in parental cells. There was no selective effect of the Pgp inhibitor PSC-833 or other Pgp modulators on LDL receptor activity in Pgp positive cells. Since also resistant Pgp, multidrug resistance protein 1, and breast cancer resistance protein negative cells exhibited an elevated LDL receptor activity, we conclude that overexpression of these proteins is not the mechanism behind the elevated LDL uptake in the drug resistant leukemic cell lines. The findings are of interest for the concept of using lipoproteins as carriers of cytotoxic drugs in cancer treatment.
Division of Clinical Pharmacology, Department of Medicine, Karolinska Institute & Hospital, Stockholm, Sweden. loukas.tatidis@ks.se
Loukas
L
Tatidis
Michèle
M
Masquelier
Sigurd
S
Vitols
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007938:Leukemia; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008560:Membrane Fluidity; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D013261:Sterols / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003524:Cyclosporins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D013261:Sterols; D002784:Cholesterol; D014700:Verapamil; D006903:Hydroxymethylglutaryl CoA Reductases; C070272:valspodar