Differential Roles of p21Waf1 and p27Kip1in Modulating Chemosensitivity and Their Possible Application in Drug Discovery Studies

• Published in: Molecular pharmacology 2001-11, Vol.60 (5), p.900-906
• Main Authors: Schmidt, Mathias, Lu, Yang, Parant, John M., Lozano, Guillermina, Bacher, Gerald, Beckers, Thomas, Fan, Zhen
• Format: Article
• Language: English
• Subjects: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; CDK; cyclin-dependent kinase; D-24851; glutathione S-transferase; GST; MTT; N-[pyridin-4-yl]-[1-[4-chlorbenzyl]-indol-3-yl]-glyoxyl-amid; retinoblastoma
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1016/S0026-895X(24)12498-4

In this study, the differential role of the cyclin-dependent kinase (CDK) inhibitors p21Waf1 and p27Kip1 in cell cycle regulation was proposed for use in screening natural or synthetic compounds for cell cycle-dependent (particularly M phase-dependent) antineoplastic activity. p21Waf1 or p27Kip1 was ectopically expressed with an ecdysone-inducible mammalian expression system in a human colon adenocarcinoma cell line. Induction of p21Waf1 or p27Kip1 expression inhibited the activities of CDK2 and completely arrested cells at G1 phase of the cell cycle by p27Kip1 and at G1 and G2 phases by p21Waf1. We examined the sensitivity of these cells to several antineoplastic agents known to be cell cycle-dependent or -independent. Substantially increased resistance to cell cycle-dependent antineoplastic agents was found in the cells when the expression of p21Waf1 or p27Kip1 was induced. In contrast, only a desensitization to cell cycle-independent antineoplastic agents was found in the cells arrested by p21Waf1 or p27Kip1. Because p21Waf1 induces an additional block at G2 phase that inhibits cell entry into M phase, we further examined the difference between p21Waf1- and p27Kip1-induced cells in their sensitivity to D-24851, a novel M phase-dependent compound. We found that induction of p21Waf1 after exposure of the cells to D-24851 conferred stronger resistance than did induction of p27Kip1. Taken together, our results suggest that the differential effect of p21Waf1 and p27Kip1 on cell cycle regulation may be advantageous for screening chemical libraries for novel antineoplastic candidates that are cell cycle-dependent, and M phase-dependent in particular.