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2014 ; 5
(5
): e1204
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Quantitative multi-parametric evaluation of centrosome declustering drugs:
centrosome amplification, mitotic phenotype, cell cycle and death
#MMPMID24787016
Ogden A
; Cheng A
; Rida PC
; Pannu V
; Osan R
; Clewley R
; Aneja R
Cell Death Dis
2014[May]; 5
(5
): e1204
PMID24787016
show ga
Unlike normal cells, cancer cells contain amplified centrosomes and rely on
centrosome clustering mechanisms to form a pseudobipolar spindle that circumvents
potentially fatal spindle multipolarity (MP). Centrosome clustering also promotes
low-grade chromosome missegregation, which can drive malignant transformation and
tumor progression. Putative 'centrosome declustering drugs' represent a cancer
cell-specific class of chemotherapeutics that produces a common phenotype of
centrosome declustering and spindle MP. However, differences between individual
agents in terms of efficacy and phenotypic nuances remain unexplored. Herein, we
have developed a conceptual framework for the quantitative evaluation of
centrosome declustering drugs by investigating their impact on centrosomes,
clustering, spindle polarity, cell cycle arrest, and death in various cancer cell
lines at multiple drug concentrations over time. Surprisingly, all centrosome
declustering drugs evaluated in our study were also centrosome-amplifying drugs
to varying extents. Notably, all declustering drugs induced spindle MP, and the
peak extent of MP positively correlated with the induction of hypodiploid
DNA-containing cells. Our data suggest acentriolar spindle pole amplification as
a hitherto undescribed activity of some declustering drugs, resulting in spindle
MP in cells that may not have amplified centrosomes. In general, declustering
drugs were more toxic to cancer cell lines than non-transformed ones, with some
exceptions. Through a comprehensive description and quantitative analysis of
numerous phenotypes induced by declustering drugs, we propose a novel framework
for the assessment of putative centrosome declustering drugs and describe
cellular characteristics that may enhance susceptibility to them.