An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells.
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.
Kwong
Joseph
J
Centre for Cancer and Inflammation, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, UK.
Kulbe
Hagen
H
Wong
Donald
D
Chakravarty
Probir
P
Balkwill
Fran
F
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; C540323:CTCE-9908; D010455:Peptides; D019718:Receptors, CXCR4; D017239:Paclitaxel