PT  - JOURNAL ARTICLE
AU  - WeiWei Li
AU  - Jianguo Fan
AU  - Debabrata Banerjee
AU  - Joseph R. Bertino
TI  - Overexpression of p21<sup>waf1</sup> Decreases G<sub>2</sub>-M Arrest and Apoptosis Induced by Paclitaxel in Human Sarcoma Cells Lacking Both p53 and Functional Rb Protein
AID  - 10.1124/mol.55.6.1088
DP  - 1999 Jun 01
TA  - Molecular Pharmacology
PG  - 1088--1093
VI  - 55
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/55/6/1088.short
4100  - http://molpharm.aspetjournals.org/content/55/6/1088.full
SO  - Mol Pharmacol1999 Jun 01; 55
AB  - 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.