ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5fluorouracil by inhibiting repair of DNA damage.
Oncol Rep
; 47(4)2022 Apr.
Article
em En
| MEDLINE
| ID: mdl-35191521
ABSTRACT
The repair of DNA damage caused by chemotherapy in cancer cells occurs mainly at two cell cycle checkpoints (G1 and G2) and is a factor contributing to chemoresistance. Most colorectal cancers harbor mutations in p53, the main pathway involved in the G1 checkpoint, and thus, are particularly dependent on the G2 checkpoint for DNA repair. The present study examined the effect of AZD6738, a specific inhibitor of ataxia telangiectasia mutated and rad3related (ATR) involved in the G2 checkpoint, combined with 5fluorouracil (5FU), a central chemotherapeutic agent, on colorectal cancer cells. Since 5FU has a DNAdamaging effect, its combination with AZD6738 is likely to enhance the therapeutic effect. The effects of the AZD6738/5FU combination were evaluated in various colorectal cancer cells (HT29, SW480, HCT116 and DLD1 cells) by flow cytometry (HT29 cells), western blotting (HT29 cells) and watersoluble tetrazolium 1 assays (HT29, SW480, HCT116 and DLD1 cells), as well as in an experimental animal model (HT29 cells). In vitro, the AZD6738/5FU combination increased the number of mitotic cells according to flow cytometry, decreased the checkpoint kinase 1 phosphorylation levels and increased cleaved caspase3 and phosphorylated form of H2A.X variant histone levels according to western blotting, and decreased the proliferation rate of four colon cancer cell lines according to cell viability experiments. In vivo, xenografted colorectal cancer cells treated with the AZD6738/5FU combination exhibited a marked decrease in proliferation compared with the 5FU alone group. The present results suggested that AZD6738 enhanced the effect of 5FU in p53mutated colorectal cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Neoplasias do Colo
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article