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Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

ABAL, Miguel ; BRAS-GONCALVES, Rui ; JUDDE, Jean-Gabriel ; FSIHI, Hafida ; DE CREMOUX, Patricia ; LOUVARD, Daniel ; MAGDELENAT, Henri ; ROBINE, Sylvie ; POUPON, Marie-France

Oncogene, 2004-03, Vol.23 (9), p.1737-1744 [Periódico revisado por pares]

Basingstoke: Nature Publishing

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Título:
Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line
Autor: ABAL, Miguel ; BRAS-GONCALVES, Rui ; JUDDE, Jean-Gabriel ; FSIHI, Hafida ; DE CREMOUX, Patricia ; LOUVARD, Daniel ; MAGDELENAT, Henri ; ROBINE, Sylvie ; POUPON, Marie-France
Assuntos: Apoptosis ; Biological and medical sciences ; Camptothecin - analogs & derivatives ; Camptothecin - pharmacology ; Cancer therapies ; CDC2 Protein Kinase - antagonists & inhibitors ; CDC2 Protein Kinase - metabolism ; Cell activation ; Cell cycle ; Cell Cycle - drug effects ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Chemotherapy ; Colon cancer ; Colorectal cancer ; Colorectal carcinoma ; Cyclin B ; Cyclin B - metabolism ; Cyclin-dependent kinase ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-dependent kinases ; Cyclins - metabolism ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA topoisomerase ; Enzyme Activation - drug effects ; Enzyme Inhibitors - pharmacology ; Fundamental and applied biological sciences. Psychology ; Gastroenterology. Liver. Pancreas. Abdomen ; HT29 Cells ; Humans ; Irinotecan ; Kinases ; Medical sciences ; Molecular and cellular biology ; Mutation ; Mutation - genetics ; p53 Protein ; Purines - pharmacology ; Response rates ; S phase ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Tumor Suppressor Protein p53 - deficiency ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Western blotting
É parte de: Oncogene, 2004-03, Vol.23 (9), p.1737-1744
Notas: ObjectType-Article-2
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Descrição: 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 p21(WAF1/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) p21(WAF1/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.
Editor: Basingstoke: Nature Publishing
Idioma: Inglês

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Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

ABAL, Miguel ; BRAS-GONCALVES, Rui ; JUDDE, Jean-Gabriel ; FSIHI, Hafida ; DE CREMOUX, Patricia ; LOUVARD, Daniel ; MAGDELENAT, Henri ; ROBINE, Sylvie ; POUPON, Marie-France

Basingstoke: Nature Publishing

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