Abstract
Mutations in the tumor-suppressor gene p53 have been associated with advanced colorectal cancer (CRC). Irinotecan (CPT-11), a DNA topoisomerase 1 inhibitor, has been recently incorporated to the adjuvant therapy. Since the DNA-damage checkpoint depends on p53 activation, the status of p53 might critically influence the response to CPT-11. We analysed the sensitivity to CPT-11 in the human colon cancer cell line HT29 (mut p53) and its wild-type (wt)-p53 stably transfected subclone HT29-A4. Cell-cycle analysis in synchronised cells demonstrated the activation of transfected wt-p53 and a p21WAF1/CIP1-dependent cell-cycle blockage in the S phase. Activated wt-p53 increased apoptosis and enhanced sensitivity to CPT-11. In p53-deficient cells, cDNA-macroarray analysis and western blotting showed an accumulation of the cyclin-dependent kinase (cdk)1/cyclin B complex. Subsequent p53-independent activation of the cdk-inhibitor (cdk-I) p21WAF1/CIP1 prevented cell-cycle progression. Cdk1 induction was exploited in vivo to improve the sensitivity to CPT-11 by additional treatment with the cdk-I CYC-202. We demonstrate a gain of sensitivity to CPT-11 in a p53-mutated colon cancer model either by restoring wild-type p53 function or by sequential treatment with cdk-Is. Considering that mutations in p53 are among the most common genetic alterations in CRC, a therapeutic approach specifically targeting p53-deficient tumors could greatly improve the treatment outcomes.
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Acknowledgements
We thank Cyclacel for kindly providing us with CYC-202, D Rouillard for expertise in FACS analysis and Athos Gianella-Boraclori, Drs David Lane, Manuel Buchwald and Klaus-Peter Janssen for critical review. This work was supported by the Institut Curie (‘Programme Incitatif et Cooperatif’ Micrometastasis and Preclinical Pharmacology R&D Fund).
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Tumor Biology Department, Medical Section, Institute Curie-CNRS, Paris 75248, France
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Abal, M., Bras-Goncalves, R., Judde, JG. et al. Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line. Oncogene 23, 1737–1744 (2004). https://doi.org/10.1038/sj.onc.1207299
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DOI: https://doi.org/10.1038/sj.onc.1207299
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