An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells

Mol Cancer Ther. 2009 Jul;8(7):1893-905. doi: 10.1158/1535-7163.MCT-08-0966. Epub 2009 Jun 30.

Abstract

The chemokine receptor CXCR4 is expressed by malignant cells in ovarian cancer and is implicated in their growth and spread. We report here a unique mechanism of action of a small peptide antagonist of CXCR4 on ovarian cancer cells: induction of cell death by mitotic catastrophe. CTCE-9908 inhibited ovarian cancer cell migration to CXCL12, but on longer incubation, caused cell death in CXCR4-positive cells. CTCE-9908 did not cause apoptosis or cellular senescence, but induced multinucleation, G(2)-M arrest, and abnormal mitosis in ovarian cancer cells. This suggests that cell death was caused by mitotic catastrophe. Using microarray and Western blot analysis, we showed that CTCE-9908 deregulated DNA damage checkpoint proteins and spindle assembly checkpoint proteins at G(2)-M phases of the cell cycle. Combination treatment of CTCE-9908 and the drug paclitaxel led to an additive cytotoxicity that also involved mitotic catastrophe. We conclude that CTCE-9908 has a unique mechanism of action in ovarian cancer cells that seems to be CXCR4 specific.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cell Nucleus / pathology*
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • DNA Damage / drug effects
  • DNA Replication / drug effects
  • Drug Therapy, Combination
  • Female
  • Flow Cytometry
  • G2 Phase / drug effects
  • Humans
  • Mitosis / drug effects*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Paclitaxel / pharmacology
  • Peptides / pharmacology*
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Phytogenic
  • CTCE-9908
  • Peptides
  • Receptors, CXCR4
  • Paclitaxel