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Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
08:29

Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel

Published on: May 14, 2018

PDMP sensitizes neuroblastoma to paclitaxel by inducing aberrant cell cycle progression leading to hyperploidy

Anne-Jan Dijkhuis1, Karin Klappe, Susan Jacobs

  • 1Department of Cell Biology, Section Membrane Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands.

Molecular Cancer Therapeutics
|March 21, 2006
PubMed

Insights

This study shows that a glucosylceramide synthase inhibitor, when combined with paclitaxel, causes cancer cells to undergo abnormal cell division and become hyperploid, rather than inducing apoptosis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Sphingolipid metabolism, particularly ceramide conversion to glucosylceramide, is linked to multidrug resistance in cancer.
  • Inhibitors of glucosylceramide synthase are investigated as potential anti-cancer therapeutics.
  • Ceramide accumulation is a known mediator of apoptosis.

Purpose of the Study:

  • To investigate the synergistic effect of D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and paclitaxel on Neuro-2a murine neuroblastoma cells.
  • To elucidate the underlying mechanism of cell death or cell cycle alteration induced by this drug combination.

Main Methods:

  • Treatment of Neuro-2a cells with D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and paclitaxel.
  • Analysis of cell cycle progression, ploidy, and apoptosis.
  • Assessment of sphingolipid biosynthesis using ISP-1.
  • Measurement of cyclin-dependent kinase 1 and 2 activities.

Main Results:

  • The combination treatment resulted in synergistic inhibition of viable cell number increase.
  • Cells exhibited a transient mitotic arrest followed by aberrant cell cycle progression and hyperploidy.
  • Apoptosis occurred to a limited extent and was not dependent on ceramide accumulation.
  • Cyclin-dependent kinase 1 and 2 activities were synergistically decreased.

Conclusions:

  • D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol does not induce apoptosis via ceramide accumulation in paclitaxel-treated cells.
  • The drug combination leads to aberrant cell cycle progression and hyperploidy through mechanisms independent of ceramide.
  • This novel mechanism involves the modulation of cell cycle-related proteins, offering a new perspective for cancer therapy.

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