title: Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death.
abstract: Paclitaxel at low concentrations (10 nM for 20 h) induces approximately 90% mitotic block at the metaphase/anaphase transition in HeLa cells, apparently by suppressing dynamics of spindle microtubules (M. A. Jordan et al., Proc. Natl. Acad. Sci. USA, 90: 9552-9556, 1993). It is not known, however, whether inhibition of mitosis by such low paclitaxel concentrations results in cell death. In the present work, we found that after removal of paclitaxel (10 nM-1 microM), blocked cells did not resume proliferation. Instead, cells exited mitosis abnormally within 24 h. They did not progress through anaphase or cytokinesis but entered an interphase-like state (chromatin decondensed, and an interphase-like microtubule array and nuclear membranes reformed). Many cells (> or = 55%) contained multiple nuclei. Additional DNA synthesis and polyploidy did not occur. DNA degradation into nucleosome-sized fragments characteristic of apoptosis began during drug incubation and increased after drug removal. Cells died within 48-72 h. Incubation with paclitaxel (10 nM for 20 h) resulted in high intracellular drug accumulation (8.3 microM) and little efflux after paclitaxel removal; intracellular retention of paclitaxel may contribute to its efficacy. The results support the hypothesis that the most potent chemotherapeutic mechanism of paclitaxel is kinetic stabilization of spindle microtubule dynamics.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara 93106, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Jordan
authors.forename: K
authors.initials: K
authors.lastname: Wendell
authors.forename: S
authors.initials: S
authors.lastname: Gardiner
authors.forename: W B
authors.initials: WB
authors.lastname: Derry
authors.forename: H
authors.initials: H
authors.lastname: Copp
authors.forename: L
authors.initials: L
authors.lastname: Wilson
mesh_terms: D000705:Anaphase; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000633:toxicity*; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D002877:Chromosomes, Human / Q000187:drug effects / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000187:drug effects / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008677:Metaphase; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002843:Chromatin; D004273:DNA, Neoplasm; D017239:Paclitaxel