ArticleGynecologic oncology2013
Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53.
Article in Gynecologic oncology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- Exploratory Analysis of Regulated Cell Death-Related Genes as Potential Prognostic Biomarkers in Endometrial Carcinoma.Biomedicines · 2025Article
- Tumor suppressor genes in the tumor microenvironment.Disease models & mechanisms · 2025Review
- Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry.Science advances · 2024Article
- PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma.Endocrine connections · 2024Article
- Looking beyond carboplatin and paclitaxel for the treatment of advanced/recurrent endometrial cancer.Gynecologic oncology · 2022Review
- ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage.Oncology reports · 2022Article
- FOXM1 Promotes Drug Resistance in Cervical Cancer Cells by Regulating ABCC5 Gene Transcription.BioMed research international · 2022Article
- Targeting mutant p53 for cancer therapy: direct and indirect strategies.Journal of hematology & oncology · 2021Review
- Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer.Methods and protocols · 2020Article
- Review
- Clinical actionability of molecular targets in endometrial cancer.Nature reviews. Cancer · 2019Review
- Crosstalk between SOX2 and cytokine signaling in endometrial carcinoma.Scientific reports · 2018Article
- Synthetically lethal nanoparticles for treatment of endometrial cancer.Nature nanotechnology · 2018Article
- Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations.Disease markers · 2018Article
- TP53 hot spot mutations in ovarian cancer: selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas.Gynecologic oncology · 2015Article
- TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma.International journal of oncology · 2015Article
- Comprehensive profiling of EGFR/HER receptors for personalized treatment of gynecologic cancers.Molecular diagnosis & therapy · 2014Review
- Remote loading of preencapsulated drugs into stealth liposomes.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- The consequence of oncomorphic TP53 mutations in ovarian cancer.International journal of molecular sciences · 2013Review
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveEndometrial tumors with non-functional p53, such as serous uterine endometrial carcinomas, are aggressive malignancies with a poor outcome, yet they have an Achilles' heel: due to loss of p53 function, these tumors may be sensitive to treatments which abrogate the G2/M checkpoint. Our objective was to exploit this weakness to induce mitotic cell death using two strategies: (1) EGFR inhibitor gefitinib combined with paclitaxel to arrest cells at mitosis, or (2) BI2536, an inhibitor of polo-like kinase 1 (PLK1), to block PLK1 activity.
methodsWe examined the impact of combining gefitinib and paclitaxel or PLK1 inhibitor on expression of G2/M checkpoint controllers, cell viability, and cell cycle progression in endometrial cancer cells with mutant p53.
resultsIn cells lacking normal p53 activity, each treatment activated CDC25C and inactivated Wee1, which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis. Live cell imaging demonstrated irreversible mitotic arrest and eventual cell death. Combinatorial therapy with paclitaxel and gefitinib was highly synergistic and resulted in a 10-fold reduction in the IC50 for paclitaxel, from 14nM as a single agent to 1.3nM in the presence of gefitinib. However, BI2536 alone at low concentrations (5nM) was the most effective treatment and resulted in massive mitotic cell death. In a xenograft mouse model with p53-deficient cells, low dose BI2536 significantly inhibited tumor growth.
conclusionsThese findings reveal induction of mitotic cell death as a therapeutic strategy for endometrial tumors lacking functional p53.
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