Regular Article

British Journal of Cancer (1999) 81, 423–430. doi:10.1038/sj.bjc.6690711 www.bjcancer.com
Published online 10 September 1999

Preferential killing of multidrug-resistant KB cells by inhibitors of glucosylceramide synthase

Correspondence to: JR Warr

K M Nicholson1, D M Quinn1, G L Kellett1 and J R Warr1

1Department of Biology, University of York, PO Box 373, York Y010 5YW, UK

Received 26 February 1999; Revised 19 May 1999; Accepted 21 May 1999.

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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 muM PPPP. This treatment produced 75.8 (plusminus 7.1)%, 73.6 (plusminus 9.8)% and 75.3 (plusminus 6.4)% apoptotic cells in the three MDR cell lines respectively, compared to 19.0 (plusminus 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.

Keywords:

multidrug-resistance, glucosylceramide, apoptosis

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