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Molecular Pharmacology

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Research ArticleArticle

Overexpression of p21waf1 Decreases G2-M Arrest and Apoptosis Induced by Paclitaxel in Human Sarcoma Cells Lacking Both p53 and Functional Rb Protein

WeiWei Li, Jianguo Fan, Debabrata Banerjee and Joseph R. Bertino
Molecular Pharmacology June 1999, 55 (6) 1088-1093; DOI: https://doi.org/10.1124/mol.55.6.1088
WeiWei Li
Laboratory of Molecular Pharmacology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York
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Jianguo Fan
Laboratory of Molecular Pharmacology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York
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Debabrata Banerjee
Laboratory of Molecular Pharmacology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York
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Joseph R. Bertino
Laboratory of Molecular Pharmacology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York
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Abstract

We examined the effect of overexpression of p21waf1 on cytotoxicity of paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma protein and p53. Under normal growth conditions, p21waf1 is not detectable in SaOs-2 cells. Upon p21waf1 induction by tetracycline withdrawal, we observed a reduced apoptotic response to paclitaxel with a 3- to 6-fold increase in IC50 values compared with that of cells not induced by p21waf1. We also observed a 5-fold increase in the IC50 value when cytotoxicity to vincristine, another microtubule-disrupting agent, was assessed, whereas we observed a marked decrease in the IC50 value after p21waf1 induction in response to etoposide, a topoisomerase II inhibitor. After treatment with paclitaxel, less accumulation of G2-M was observed in p21waf1-induced cells compared with non-p21waf1-induced cells (57% versus 74%). p21waf1 induction also inhibited the increased cyclin B1-associated kinase activity induced by paclitaxel. Overexpression of p21waf1 in SaOs-2 cells lacking both p53 and functional retinoblastoma protein may decrease the G2-M arrest induced by paclitaxel due to suppression of the S-G2 checkpoint, resulting in a decreased apoptotic response of cells to paclitaxel.

Footnotes

    • Received January 15, 1999.
    • Accepted March 15, 1999.
  • Send reprint requests to: Dr. Joseph R. Bertino, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. E-mail: bertinoj{at}mskcc.org

  • This work was supported by United States Public Health Service Grant PO1-CA47179. J.R.B. is an American Cancer Society Professor of Medicine and Pharmacology.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (6)
Molecular Pharmacology
Vol. 55, Issue 6
1 Jun 1999
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Research ArticleArticle

Overexpression of p21waf1 Decreases G2-M Arrest and Apoptosis Induced by Paclitaxel in Human Sarcoma Cells Lacking Both p53 and Functional Rb Protein

WeiWei Li, Jianguo Fan, Debabrata Banerjee and Joseph R. Bertino
Molecular Pharmacology June 1, 1999, 55 (6) 1088-1093; DOI: https://doi.org/10.1124/mol.55.6.1088

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Research ArticleArticle

Overexpression of p21waf1 Decreases G2-M Arrest and Apoptosis Induced by Paclitaxel in Human Sarcoma Cells Lacking Both p53 and Functional Rb Protein

WeiWei Li, Jianguo Fan, Debabrata Banerjee and Joseph R. Bertino
Molecular Pharmacology June 1, 1999, 55 (6) 1088-1093; DOI: https://doi.org/10.1124/mol.55.6.1088
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