Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation: A potential early step in drug resistance

Ravat Panvichian, Kim Orth, Mark L. Day, Kathleen C. Day, Mary Josephine Pilat, Kenneth J. Pienta

Research output: Contribution to journalArticle

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Abstract

The chemotherapeutic agent paclitaxel disrupts microtubule dynamics causing mitotic arrest, which leads to cell death. However, in paclitaxel- resistant tumor cells, treatment with paclitaxel induces abnormal progression through prophase resulting in a multimininucleated phenotype. Multimininucleation and subsequent polyploidization have been correlated with paclitaxel resistance. Paclitaxel treatment of HeLa cells resulted in cell death via typical activation of the apoptotic machinery, whereas treatment of the relative paclitaxel-resistant prostate cancer cell line PC-3 induced an attenuated caspase activation and multimininucleation. The multimininucleated phenotype could be mimicked in HeLa cells treated with paclitaxel and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a peptide caspase inhibitor. Interestingly, we observed no discernible difference in the pattern of cdc-2 kinase activation or phosphorylation of bcl-2-like proteins in PC-3 and HeLa cells treated with paclitaxel, which demonstrated that these molecules could not be used as indicators for the degree of caspase activation. In this study, we establish a connection between relative paclitaxel resistance, caspase attenuation/inhibition, and the multimininucleated phenotype.

Original languageEnglish (US)
Pages (from-to)4667-4672
Number of pages6
JournalCancer Research
Volume58
Issue number20
StatePublished - Oct 15 1998

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Caspases
Paclitaxel
Drug Resistance
HeLa Cells
Phenotype
Cell Death
Prophase
Caspase Inhibitors
Microtubules
Prostatic Neoplasms
Phosphotransferases
Phosphorylation
Cell Line
Peptides

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation : A potential early step in drug resistance. / Panvichian, Ravat; Orth, Kim; Day, Mark L.; Day, Kathleen C.; Pilat, Mary Josephine; Pienta, Kenneth J.

In: Cancer Research, Vol. 58, No. 20, 15.10.1998, p. 4667-4672.

Research output: Contribution to journalArticle

Panvichian, Ravat ; Orth, Kim ; Day, Mark L. ; Day, Kathleen C. ; Pilat, Mary Josephine ; Pienta, Kenneth J. / Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation : A potential early step in drug resistance. In: Cancer Research. 1998 ; Vol. 58, No. 20. pp. 4667-4672.
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