Selective and irreversible cell cycle inhibition by diphenyleneiodonium.
Because cell proliferation is subject to checkpoint-mediated regulation of the cell cycle, pharmacophores that target cell cycle checkpoints have been used clinically to treat human hyperproliferative disorders. It is shown here that the flavoprotein inhibitor diphenyleneiodionium can block cell proliferation by targeting of cell cycle checkpoints. Brief exposure of mitotically arrested cells to diphenyleneiodonium induces a loss of the mitotic cell morphology, and this corresponds with a decrease in the levels of the mitotic markers MPM2 and phospho-histone H3, as well as a loss of centrosome maturation, spindle disassembly, and redistribution of the chromatin remodeling helicase ATRX. Surprisingly, this mitotic exit resulted in a tetraploidization that persisted long after drug release. Analogously, brief exposure to diphenyleneiodonium also caused prolonged arrest in G(1) phase. By contrast, diphenyleneiodonium exposure did not abrogate S phase, although it did result in a subsequent block of G(2) cell cycle progression. This indicates that diphenyleneiodonium selectively targets components of the cell cycle, thereby either causing cell cycle arrest, or checkpoint override followed by cell cycle arrest. These irreversible effects of diphenyleneiodonium on the cell cycle may underlie its potent antiproliferative activity.
Scaife
Robin M
RM
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, Centre for Medical Research, The University of Western Australia. rscaife@cyllene.uwa.edu.au
D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008677:Metaphase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism
D015415:Biomarkers; D002843:Chromatin; D009861:Onium Compounds; C007517:diphenyleneiodonium; D017239:Paclitaxel; D015739:Nocodazole