Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells
| Autor: | M, Gupta, S, Fan, Q, Zhan, K W, Kohn, P M, O'Connor, Y, Pommier |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Neoplasms
Hormone-Dependent Recombinant Fusion Proteins Breast Neoplasms DNA Fragmentation Adenocarcinoma Transfection Tumor Cells Cultured Humans Enzyme Inhibitors Tumor Stem Cell Assay Nocodazole G1 Phase Estrogens DNA Neoplasm Oncogene Proteins Viral Flow Cytometry Genes p53 Antineoplastic Agents Phytogenic Neoplasm Proteins Repressor Proteins Colonic Neoplasms Camptothecin Female Topoisomerase I Inhibitors Tumor Suppressor Protein p53 DNA Damage |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 3(9) |
| ISSN: | 1078-0432 |
| Popis: | Camptothecin (CPT) derivatives are topoisomerase I (top1) inhibitors recently introduced as clinical agents. To explore the role of p53 in CPT-induced cytotoxicity, we examined CPT effects in two isogenic pairs of human cancer cell lines, MCF-7 breast carcinoma and HCT116 colon carcinoma cells, in which p53 function had been disrupted by transfection with the human papillomavirus type-16 E6 gene. Clonogenic survival assays showed that both MCF-7/E6 and HCT116/E6 cells were more sensitive to CPT. No differences in top1 protein levels and activity analyzed by a novel in vitro oligonucleotide assay were observed in the E6 transfectants. Also, CPT showed comparable top1 cleavable complex formation in vivo, as determined by DNA single-strand breaks and DNA protein cross-links. These results suggest that p53 can protect against CPT-induced cytotoxicity and that this protection is mediated downstream of CPT-induced DNA damage. Flow cytometry analyses showed that CPT can induce G1 arrest in cells with normal p53. This G1 arrest was markedly reduced in the p53-deficient cells. These results demonstrate a critical role of p53 as a G1 checkpoint regulator after CPT-induced DNA damage and suggest a rationale for the selectivity of CPT toward tumors with p53 mutations. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|