title: Preferential killing of multidrug-resistant KB cells by inhibitors of glucosylceramide synthase.
abstract: This study has compared the preferential killing of three multidrug-resistant (MDR) KB cell lines, KB-C1, KB-A1 and KB-V1 by two inhibitors of glucosylceramide synthase, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP), to the killing produced by these compounds in the drug-sensitive cell line, KB-3-1. Both of the inhibitors caused much greater induction of apoptosis in each of the three MDR cell lines than in the drug-sensitive cell line, as judged by morphological assay and confirmed by poly-(ADP-ribose)-polymerase cleavage. The highest level of apoptosis was produced following 24-h exposure to 5 microM PPPP. This treatment produced 75.8 (+/- 7.1)%, 73.6 (+/- 9.8)% and 75.3 (+/- 6.4)% apoptotic cells in the three MDR cell lines respectively, compared to 19.0 (+/- 9.8)% in the drug-sensitive cell line. A reduction in glucosylceramide level following inhibitor treatment occurred in KB-3-1 cells as well as in the MDR cell lines, suggesting that the increased apoptotic response in the MDR cells reflected a different downstream response to changes in the levels of this lipid in these cells compared to that in the drug-sensitive cells. These results suggest that the manipulation of glucosylceramide levels may be a fruitful way of causing the preferential killing of MDR cells in vitro and possibly in vivo.
authors.affiliation: Department of Biology, University of York, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Nicholson
authors.forename: D M
authors.initials: DM
authors.lastname: Quinn
authors.forename: G L
authors.initials: GL
authors.lastname: Kellett
authors.forename: J R
authors.initials: JR
authors.lastname: Warr
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005963:Glucosylceramides / Q000378:metabolism*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D007624:KB Cells / Q000187:drug effects* / Q000473:pathology; D050356:Lipid Metabolism; D009025:Morpholines / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*
chemical_list: C110417:1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D009025:Morpholines; D009363:Neoplasm Proteins; D011412:Propanolamines; D011759:Pyrrolidines; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D011065:Poly(ADP-ribose) Polymerases