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ICRF-193, an Anticancer Topoisomerase II Inhibitor, Induces Arched Telophase Spindles That Snap, Leading to a Ploidy Increase in Fission Yeast

ICRF-193, an Anticancer Topoisomerase II Inhibitor, Induces Arched Telophase Spindles That Snap, Leading to a Ploidy Increase in Fission Yeast

Norihiko Nakazawa, Rajesh Mehrotra, Orie Arakawa, Mitsuhiro Yanagida

Genes Cells. 2016 Sep;21(9):978-93.

PMID: 27458047

Abstract:

ICRF-193 [meso-4,4-(2,3-butanediyl)-bis(2,6-piperazinedione)] is a complex-stabilizing inhibitor of DNA topoisomerase II (topo II) that is used as an effective anticancer drug. ICRF-193 inhibits topo II catalytic activity in vitro and blocks nuclear division in vivo. Here, we examined the effects of ICRF-193 treatment on chromatin behavior and spindle dynamics using detailed live mitotic cell analysis in the fission yeast, Schizosaccharomyces pombe. Time-lapse movie analysis showed that ICRF-193 treatment leads to an elongation of presumed chromatin fibers connected to kinetochores during mid-mitosis. Anaphase spindles begin to arch, and eventually spindle poles come together abruptly, as if the spindle snapped at the point of spindle microtubule overlap in telophase. Segregating chromosomes appeared as elastic clumps and subsequently pulled back and merged. The snapped spindle phenotype was abolished by microtubule destabilization after thiabendazole treatment, accompanied by unequal chromosome segregation or severe defects in spindle extension. Thus, we conclude that ICRF-193-treated, unseparated sister chromatids pulling toward opposite spindle poles produce the arched and snapped telophase spindle. ICRF-193 treatment increased DNA content, suggesting that the failure of sister chromatids to separate properly in anaphase, causes the spindle to break in telophase, resulting in polyploidization.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP21416886	ICRF-193		21416-88-6	Price

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