title: Phenolphthalein induces centrosome amplification and tubulin depolymerization in vitro.
abstract: Aneuploidy is a major cause of human reproductive failure and plays a large role in cancer. Phenolphthalein (PHT) induces tumors in rodents but its primary mechanism does not seem to be DNA damage. In heterozygous TSG-p53(®) mice, PHT induces lymphomas and also micronuclei (MN), many containing kinetochores (K), implying chromosome loss (aneuploidy). The induction of aneuploidy would be compatible with the loss of the normal p53 gene seen in the lymphomas. In this study, we confirm PHT's aneugenicity and determine the aneugenic mechanism of PHT by combining traditional genetic toxicology assays with image and flow cytometry methods. The data revealed that PHT induces tubulin polymerization abnormalities and deregulates the centrosome duplication cycle causing centrosome amplification. We also show that one of the consequences of these events is apoptosis.
authors.affiliation: Pfizer Worldwide Research and Development, Genetic Toxicology Center of Emphasis, Groton, Connecticut, USA. pamela.heard@pfizer.com
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Heard
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Rubitski
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spellman
authors.forename: Maik J
authors.initials: MJ
authors.lastname: Schuler
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D018385:Centrosome / Q000187:drug effects*; D006224:Cricetinae; D005434:Flow Cytometry; D006801:Humans; D007202:Indicators and Reagents / Q000494:pharmacology*; D051379:Mice; D009152:Mutagenicity Tests; D020113:Phenolphthalein / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects*
chemical_list: D007202:Indicators and Reagents; D014404:Tubulin; D020113:Phenolphthalein