ArticleInvestigational new drugs2011
A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe.
Article in Investigational new drugs, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 50 citations in OpenAlex.
- Multiple Regulatory Mechanisms of Post-Translational Modifications and Therapeutic Potential of Mitotic Catastrophe.International journal of molecular sciences · 2026Review
- Review
- Non-Canonical Programmed Cell Death in Colon Cancer.Cancers · 2022Review
- The Influence of Cell Cycle Regulation on Chemotherapy.International journal of molecular sciences · 2021Review
- Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Review
- Repurposing DNA repair factors to eradicate tumor cells upon radiotherapy.Translational cancer research · 2017Article
- Review
- MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.Oncotarget · 2016Article
- Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.International journal of molecular sciences · 2016Review
- Modulation of RhoA GTPase Activity Sensitizes Human Cervix Carcinoma Cells to γ-Radiation by Attenuating DNA Repair Pathways.Oxidative medicine and cellular longevity · 2016Article
- Ataxia-telangiectasia: future prospects.The application of clinical genetics · 2014Review
- Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising.Frontiers in oncology · 2014Review
- Chk1 inhibition in p53-deficient cell lines drives rapid chromosome fragmentation followed by caspase-independent cell death.Cell cycle (Georgetown, Tex.) · 2014Article
- Chk1/2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53.Molecular cancer therapeutics · 2013Article
- Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2.PloS one · 2013Article
- Characterization of DDRI-18 (3,3'-(1H,3'H-5,5'-bibenzo[d]imidazole-2,2'-diyl)dianiline), a novel small molecule inhibitor modulating the DNA damage response.British journal of pharmacology · 2012Article
- DNA damage response pathways and cell cycle checkpoints in colorectal cancer: current concepts and future perspectives for targeted treatment.Current cancer drug targets · 2012Review
- Premature chromosome condensation induced by caffeine, 2-aminopurine, staurosporine and sodium metavanadate in S-phase arrested HeLa cells is associated with a decrease in Chk1 phosphorylation, formation of phospho-H2AX and minor cytoskeletal rearrangements.Histochemistry and cell biology · 2011Article
- Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy.Molecular & cellular oncologyReview
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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