ArticleMolecular pharmacology2009
90-kDa heat shock protein inhibition abrogates the topoisomerase I poison-induced G2/M checkpoint in p53-null tumor cells by depleting Chk1 and Wee1.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 44 citations in OpenAlex.
- Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells.Journal of lasers in medical sciences · 2022Article
- PKMYT1 as a Potential Target to Improve the Radiosensitivity of Lung Adenocarcinoma.Frontiers in genetics · 2020Article
- DAF-21/Hsp90 is required for C. elegans longevity by ensuring DAF-16/FOXO isoform A function.Scientific reports · 2018Article
- Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases.Molecules (Basel, Switzerland) · 2017Review
- Re-examining HSPC1 inhibitors.Cell stress & chaperones · 2017Article
- Rational Combinations of Targeted Agents in AML.Journal of clinical medicine · 2015Review
- Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.Pharmacology & therapeutics · 2014Review
- Molecular targets and mechanisms of radiosensitization using DNA damage response pathways.Future oncology (London, England) · 2013Review
- Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin.Molecular cancer · 2012Article
- Cooperative enhancement of radiosensitivity after combined treatment of 17-(allylamino)-17-demethoxygeldanamycin and celecoxib in human lung and colon cancer cell lines.DNA and cell biology · 2012Article
- High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.PloS one · 2011Article
- Antiproliferative and proapoptotic activity of GUT-70 mediated through potent inhibition of Hsp90 in mantle cell lymphoma.British journal of cancer · 2011Article
- Targeting the dynamic HSP90 complex in cancer.Nature reviews. Cancer · 2010Review
- New insights into checkpoint kinase 1 in the DNA damage response signaling network.Clinical cancer research : an official journal of the American Association for Cancer Research · 2010Review
- Macrocyclic inhibitors of hsp90.Current topics in medicinal chemistry · 2010Review
- Centrosome-associated regulators of the G(2)/M checkpoint as targets for cancer therapy.Molecular cancer · 2009Review
- Update on Hsp90 inhibitors in clinical trial.Current topics in medicinal chemistry · 2009Review
- A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2008Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The G(2)/M cell cycle checkpoint is regulated by a multitude of signaling pathways after genotoxic stress. Herein, we report that treatment with the 90-kDa heat shock protein (Hsp90) molecular chaperone inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) selectively abrogates the G(2)/M checkpoint induced by 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, in p53-null compared with p53-intact HCT116 colon cancer cells. The basis for this selectivity can be explained in part by the lack of p21 induction in p53-null cells. In accord with published results, we could show that treatment with 17AAG resulted in depletion of Chk1, a known Hsp90 client protein. In addition, we observed a time- and dose-dependent decrease in Wee1 kinase level, a negative regulator of mitosis, after 17AAG treatment in gastrointestinal cancer cells. Depletion of Wee1 protein preceded mitotic entry induced by 17AAG, and this decrease could be partially rescued by cotreatment with a proteasome inhibitor. Coimmunoprecipitation experiments showed that Hsp90 and Wee1 interacted in whole cells, and 17AAG treatment decreased the degradative half-life of Wee1, indicating that Wee1 is another Hsp90 client in mammalian cells. Knockdown of Chk1 and Wee1 by short interfering RNA each resulted in abrogation of the G(2)/M checkpoint induced by SN-38. The combination of SN-38 and 17AAG was shown to be synergistic in p53-null but not in parental HCT116 cells by median effect/combination index analysis. Taken together, 17AAG specifically inhibits the G(2)/M checkpoint in p53-defective cells by down-regulation of two critical checkpoint kinases, Chk1 and Wee1.
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