Centrosome amplification (CA) and resultant
chromosomal instability have long been associated with
tumorigenesis. However, exacerbation of CA and relentless centrosome declustering engender robust spindle multipolarity (SM) during mitosis and may induce cell death. Recently, we demonstrated that a noscapinoid member, reduced bromonoscapine, (S)-3-(R)-9-bromo-5-(4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo-[4,5-g]
isoquinoline (
Red-Br-nos), induces
reactive oxygen species (ROS)-mediated autophagy and
caspase-independent death in
prostate cancer PC-3 cells. Herein, we show that
Red-Br-nos induces ROS-dependent DNA damage that resulted in high-grade CA and SM in PC-3 cells. Unlike
doxorubicin, which causes double-stranded DNA breaks and chronic G2 arrest accompanied by 'templated' CA,
Red-Br-nos-mediated DNA damage elicits de novo CA during a transient S/G2 stall, followed by checkpoint abrogation and mitotic entry to form aberrant mitotic figures with supernumerary spindle poles. Attenuation of multipolar phenotype in the presence of
tiron, a ROS inhibitor, indicated that ROS-mediated DNA damage was partly responsible for driving CA and SM. Although a few cells (∼5%) yielded to aberrant cytokinesis following an 'anaphase catastrophe', most mitotically arrested cells (∼70%) succumbed to 'metaphase catastrophe,' which was
caspase-independent. This report is the first documentation of rapid de novo centrosome formation in the presence of parent centrosome by a noscapinoid family member, which triggers death-inducing SM via a unique mechanism that distinguishes it from other ROS-inducers, conventional
DNA-damaging agents, as well as other microtubule-binding drugs.