ArticleJournal of ovarian research2016
Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer.
Article in Journal of ovarian research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Accuracy of analysis of cfDNA for detection of single nucleotide variants and copy number variants in breast cancer.BMC cancer · 2019Pooled it
- Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C.British journal of cancer · 2026Article
- Molecular Mechanisms of Synergistic Effect of PRIMA-1Cancer medicine · 2025Article
- APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy.Molecular cancer therapeutics · 2023Article
- DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities.Cancers · 2023Review
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- TP53-Mutated Myelodysplasia and Acute Myeloid Leukemia.Mediterranean journal of hematology and infectious diseases · 2023Review
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- Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246-Sensitive Disease Subtype.Molecular cancer therapeutics · 2022Article
- Interrogating the Genomic Landscape of Uterine Leiomyosarcoma: A Potential for Patient Benefit.Cancers · 2022Review
- Article
- APR-246-The Mutant TP53 Reactivator-Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells.Biomolecules · 2022Article
- APR-246 induces apoptosis and enhances chemo-sensitivity via activation of ROS and TAp73-Noxa signal in oesophageal squamous cell cancer with TP53 missense mutation.British journal of cancer · 2021Article
- Rapid Evaluation of Small Molecule Cellular Target Engagement with a Luminescent Thermal Shift Assay.ACS medicinal chemistry letters · 2021Article
- Programmed cell death, redox imbalance, and cancer therapeutics.Apoptosis : an international journal on programmed cell death · 2021Review
- Opportunities for Ferroptosis in Cancer Therapy.Antioxidants (Basel, Switzerland) · 2021Article
- CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer.International journal of molecular sciences · 2021Article
- Rely on Each Other: DNA Binding Cooperativity Shapes p53 Functions in Tumor Suppression and Cancer Therapy.Cancers · 2021Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMutation in the tumor suppressor gene TP53 is an early event in the development of high-grade serous (HGS) ovarian cancer and is identified in more than 96 % of HGS cancer patients. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 protein by refolding it to wild type conformation, thus inducing apoptosis. APR-246 has been tested as monotherapy in a Phase I/IIa clinical study in hematological malignancies and prostate cancer with promising results, and a Phase Ib/II study in combination with platinum-based therapy in ovarian cancer is ongoing. In the present study, we investigated the anticancer effects of APR-246 in combination with conventional chemotherapy in primary cancer cells isolated from ascitic fluid from 10 ovarian, fallopian tube, or peritoneal cancer patients, 8 of which had HGS cancer.
methodsCell viability was assessed with fluorometric microculture cytotoxicity assay (FMCA) and Combination Index was calculated using the Additive model. p53 status was determined by Sanger sequencing and single strand conformation analysis, and p53 protein expression by western blotting.
resultsWe observed strong synergy with APR-246 and cisplatin in all tumor samples carrying a TP53 missense mutation, while synergistic or additive effects were found in cells with wild type or TP53 nonsense mutations. Strong synergy was also observed with carboplatin or doxorubicin. Moreover, APR-246 sensitized TP53 mutant primary ovarian cancer cells, isolated from a clinically platinum-resistant patient, to cisplatin; the IC50 value of cisplatin decreased 3.6 fold from 6.5 to 1.8 μM in the presence of clinically relevant concentration of APR-246.
conclusionThese results suggest that combination treatment with APR-246 and DNA-damaging drugs could significantly improve the treatment of patients with TP53 mutant HGS cancer, and thus provide strong support for the ongoing clinical study with APR-246 in combination with carboplatin and pegylated liposomal doxorubicin in patients with recurrent HGS cancer.
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