| Title |
A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe
|
|---|---|
| Published in |
Investigational New Drugs, December 2009
|
| DOI | 10.1007/s10637-009-9361-2 |
| Pubmed ID | |
| Authors |
Oliver Riesterer, Fumihiko Matsumoto, Li Wang, Jessica Pickett, David Molkentine, Uma Giri, Luka Milas, Uma Raju |
| Abstract |
Check point kinases (Chk) play a major role in facilitating DNA repair upon radiation exposure. We tested the potency of a novel inhibitor of Chk1 and Chk2, XL-844 (provided by Exelixis Inc., CA, USA), to radiosensitize human cancer cells grown in culture and investigated the underlying mechanisms. HT-29 cells (a human colon cancer line) were exposed to XL-844, radiation, or both, and assessed for clonogenic cell survival. Treatment-dependent effects on phosphorylated forms of Chk proteins were assessed by Western blots. Further mechanistic investigations in HT-29 cells included cell cycle analysis by flowcytometry and assessment of DNA repair kinetics by immuno-cytochemistry (ICC) for nuclear appearance of the phosphorylated form of histone 2AX protein (γ-H2AX) staining. Cells undergoing mitotic catastrophe were identified by irregular pattern of mitotic spindle markers α and γ-tubulin staining by ICC. XL-844 enhanced radiosensitivity in a dose and schedule-dependent manner and the enhancement factor was 1.42 at 0.5 survival fraction. Mechanistically XL-844 abrogated radiation-induced Chk2 phosphorylation, induced pan-nuclear γ-H2AX, and prolonged the presence of radiation-induced γ-H2AX foci, and promoted mitotic catastrophe. In conclusion, our data showed that inhibition of Chk2 activity by XL-844 enhanced cancer cell radiosensitivity that was associated with inhibition of DNA repair and induction of mitotic catastrophe. |
Mendeley readers
The data shown below were compiled from readership statistics for 33 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 3% |
| Unknown | 32 | 97% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 13 | 39% |
| Student > Ph. D. Student | 5 | 15% |
| Student > Bachelor | 3 | 9% |
| Student > Master | 3 | 9% |
| Student > Doctoral Student | 1 | 3% |
| Other | 2 | 6% |
| Unknown | 6 | 18% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 9 | 27% |
| Agricultural and Biological Sciences | 9 | 27% |
| Chemistry | 3 | 9% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 6% |
| Medicine and Dentistry | 2 | 6% |
| Other | 1 | 3% |
| Unknown | 7 | 21% |
Attention Score in Context
This research output has an Altmetric Attention Score of 6. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 September 2022.
All research outputs
#4,849,926
of 23,371,053 outputs
Outputs from Investigational New Drugs
#171
of 1,191 outputs
Outputs of similar age
#27,617
of 166,692 outputs
Outputs of similar age from Investigational New Drugs
#4
of 16 outputs
Altmetric has tracked 23,371,053 research outputs across all sources so far. Compared to these this one has done well and is in the 76th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,191 research outputs from this source. They receive a mean Attention Score of 4.8. This one has done well, scoring higher than 78% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 166,692 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 78% of its contemporaries.
We're also able to compare this research output to 16 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 56% of its contemporaries.