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Cell Death Dis. 2014 Nov 20;5:e1538. doi: 10.1038/cddis.2014.505.

Centrosome-declustering drugs mediate a two-pronged attack on interphase and mitosis in supercentrosomal cancer cells.

Author information

1
Department of Biology, Georgia State University, Atlanta, GA, USA.
2
University of Gynecologic Oncology, Northside Hospital Cancer Institute, Atlanta, GA, USA.
3
Center for Molecular Medicine of the University of Cologne, Cologne, Germany.

Abstract

Classical anti-mitotic drugs have failed to translate their preclinical efficacy into clinical response in human trials. Their clinical failure has challenged the notion that tumor cells divide frequently at rates comparable to those of cancer cells in vitro and in xenograft models. Given the preponderance of interphase cells in clinical tumors, we asked whether targeting amplified centrosomes, which cancer cells carefully preserve in a tightly clustered conformation throughout interphase, presents a superior chemotherapeutic strategy that sabotages interphase-specific cellular activities, such as migration. Herein we have utilized supercentrosomal N1E-115 murine neuroblastoma cells as a test-bed to study interphase centrosome declustering induced by putative declustering agents, such as Reduced-9-bromonoscapine (RedBr-Nos), Griseofulvin and PJ-34. We found tight 'supercentrosomal' clusters in the interphase and mitosis of ~80% of patients' tumor cells with excess centrosomes. RedBr-Nos was the strongest declustering agent with a declustering index of 0.36 and completely dispersed interphase centrosome clusters in N1E-115 cells. Interphase centrosome declustering caused inhibition of neurite formation, impairment of cell polarization and Golgi organization, disrupted cellular protrusions and focal adhesion contacts-factors that are crucial prerequisites for directional migration. Thus our data illustrate an interphase-specific potential anti-migratory role of centrosome-declustering agents in addition to their previously acknowledged ability to induce spindle multipolarity and mitotic catastrophe. Centrosome-declustering agents counter centrosome clustering to inhibit directional cell migration in interphase cells and set up multipolar mitotic catastrophe, suggesting that disbanding the nuclear-centrosome-Golgi axis is a potential anti-metastasis strategy.

PMID:
25412316
PMCID:
PMC4260758
DOI:
10.1038/cddis.2014.505
[Indexed for MEDLINE]
Free PMC Article

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