Unknown

Dataset Information

0

AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells.


ABSTRACT: AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 ?M to 3.5 ?M. Flow cytometry showed a significant increase in the mitotic marker pHH3 (3.4% vs. 56.2%) and DS-DNA break marker ?H2AX (5.1% vs. 50.7%) for combination therapy compared with 5-FU alone. Combination therapy also increased the amount of caspase-3 dependent apoptosis compared with 5-FU alone (4% vs. 13%). The addition of exogenous nucleosides to combination therapy significantly rescued the increased DS-DNA breaks and caspase-3 dependent apoptosis almost to the levels of 5-FU monotherapy. In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells. This finding is important for designers of future clinical trials when considering the optimal timing and duration of AZD1775 treatment.

SUBMITTER: Webster PJ 

PROVIDER: S-EPMC5736347 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

altmetric image

Publications

AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells.

Webster Peter John PJ   Littlejohns Anna Tiffany AT   Gaunt Hannah Jane HJ   Prasad K Raj KR   Beech David John DJ   Burke Dermot Anthony DA  

Cell cycle (Georgetown, Tex.) 20171109 22


AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC<sub>50</sub>  ...[more]

Similar Datasets

| S-EPMC3546971 | biostudies-literature
| S-EPMC4330366 | biostudies-literature
| S-EPMC7337936 | biostudies-literature
2024-12-01 | GSE250321 | GEO
| S-EPMC3638355 | biostudies-literature
| S-EPMC6345769 | biostudies-literature
| S-EPMC4320661 | biostudies-literature
| S-EPMC9117546 | biostudies-literature
| S-EPMC9295824 | biostudies-literature
| S-EPMC6525190 | biostudies-literature