Defective G1-S cell cycle checkpoint function sensitizes cells to microtubule inhibitor-induced apoptosis.

Stewart ZA, Mays D, Pietenpol JA
Cancer Res. 1999 59 (15): 3831-7

PMID: 10447002

Defective cell cycle checkpoint function has been linked to enhanced sensitivity of tumor cells to certain genotoxic agents. To determine whether loss of the G1-S checkpoint function would sensitize tumor cells to microtubule inhibitor (MTI)-induced apoptosis, we examined the effect of the MTIs, Taxol and vincristine, on the cell cycle kinetics and survival of two isogenic cell lines, HCT116 p21+/+ and HCT116 p21-/-, which differ only at the p21 locus. p21-deficient cells displayed a dose-dependent, enhanced chemosensitivity to MTIs in both monolayer and soft agar assays as well as in mice xenograft tumors. The increased sensitivity of the p21-deficient cells to MTIs correlated with prolonged cyclin B1/Cdc2 activity and the occurrence of endoreduplication. Furthermore, sensitivity of p53-deficient cells to MTI-induced apoptosis was significantly reduced by induction of ectopic p21 protein. The results suggest that the status of G1-S checkpoint function in tumor cells may be an important determinant in the efficacy of MTIs used clinically.

MeSH Terms (22)

Animals Antineoplastic Agents, Phytogenic Apoptosis Carcinoma CDC2 Protein Kinase Colonic Neoplasms Cyclin-Dependent Kinase Inhibitor p21 Cyclin B Cyclin B1 Cyclins Ecdysterone Female G1 Phase Mice Mice, Nude Microtubules Neoplasm Proteins Neoplasm Transplantation Paclitaxel S Phase Tumor Cells, Cultured Vincristine

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