A multistep model for paclitaxel-induced apoptosis in human breast cancer cell lines

April L. Blajeski, Timothy J. Kottke, Scott H. Kaufmann

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Despite extensive previous investigation, the events occurring between paclitaxel-induced mitotic arrest and the subsequent onset of apoptosis remain incompletely understood. In the present study, the sequential morphological and biochemical changes that occur after paclitaxel treatment were examined in MDA-MB-468 (p53 mutant) and MCF-7 (p53 wild-type) breast cancer cells. Flow cytometry indicated that paclitaxel induces tetraploidy that persists until the onset of apoptosis in both cell lines. Light and electron microscopy indicated that the cells transiently arrest in mitosis and then enter a multinucleated interphase state characterized by the absence of punctate staining for CENP-F, a G2 marker, but the presence of cyclin E, a G1 cyclin, and p21waf1/cip1, a cyclin-dependent kinase inhibitor. Despite high p21waf1/cip1 levels, paclitaxel-treated cells incorporated thymidine into DNA. Aphidicolin inhibited this DNA synthesis but not the subsequent onset of apoptosis. Conversely, the broad-spectrum caspase inhibitor benzyloxycarbonyl-val-ala-asp(OMe)-fluoromethylketone inhibited apoptosis and enhanced the number of multinucleated cells but did not facilitate generation of octaploid cells. These results are consistent with a multistep model in which breast cancer cells exposed to paclitaxel undergo an aberrant mitotic exit; proceed through a tetraploid, multinucleated G1 state; initiate an aphidicolin-suppressible process of DNA repair; and subsequently undergo apoptosis.

Original languageEnglish (US)
Pages (from-to)277-288
Number of pages12
JournalExperimental Cell Research
Volume270
Issue number2
DOIs
StatePublished - Nov 1 2001

Keywords

  • Apoptosis
  • MDA-MB-468
  • Multinucleation
  • Paclitaxel

ASJC Scopus subject areas

  • Cell Biology

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