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

K M Nicholson1, D M Quinn, G L Kellett

  • 1Department of Biology, University of York, UK.

British Journal of Cancer
|October 3, 1999
PubMed

Insights

Glucosylceramide synthase inhibitors like PPPP preferentially induce apoptosis in multidrug-resistant (MDR) cancer cells. This suggests targeting glucosylceramide levels could be a strategy for selective MDR cell killing.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancer poses a significant therapeutic challenge.
  • Targeting specific metabolic pathways offers potential strategies to overcome MDR.

Purpose of the Study:

  • To compare the efficacy of glucosylceramide synthase inhibitors (PDMP and PPPP) in inducing apoptosis in MDR KB cell lines versus drug-sensitive cells.
  • To investigate the role of glucosylceramide levels in the differential response of MDR cells to these inhibitors.

Main Methods:

  • Treatment of three MDR KB cell lines (KB-C1, KB-A1, KB-V1) and one drug-sensitive KB-3-1 cell line with PDMP and PPPP.
  • Assessment of apoptosis induction via morphological assays and poly-(ADP-ribose)-polymerase (PARP) cleavage.
  • Measurement of glucosylceramide levels following inhibitor treatment.

Main Results:

  • Both PDMP and PPPP induced significantly higher levels of apoptosis in MDR cell lines compared to the drug-sensitive cell line.
  • Optimal apoptosis induction (75.8%) was observed in MDR cells after 24-hour exposure to 5 microM PPPP.
  • Inhibitor treatment reduced glucosylceramide levels in both sensitive and resistant cells, indicating differential downstream signaling.

Conclusions:

  • Glucosylceramide synthase inhibitors demonstrate preferential killing of MDR cancer cells.
  • Modulating glucosylceramide levels presents a promising approach for selective MDR cell elimination in vitro and potentially in vivo.

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