Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells
| Autor: | Stjepan Uldrijan, Iva Slaninová, Petr Bartůněk, Antonio R. Pombinho, Zuzana Mrkvová |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
p53
MDMX Pharmaceutical Science Cell Cycle Proteins Analytical Chemistry 0302 clinical medicine Drug Discovery Mitotic catastrophe 0303 health sciences biology drug repurposing Chemistry Melanoma Nuclear Proteins Proto-Oncogene Proteins c-mdm2 3. Good health Gene Expression Regulation Neoplastic Chemistry (miscellaneous) 030220 oncology & carcinogenesis MCF-7 Cells Molecular Medicine Mdm2 Cell Survival Down-Regulation Albendazole Article lcsh:QD241-441 03 medical and health sciences Multinucleate Downregulation and upregulation lcsh:Organic chemistry Cell Line Tumor Proto-Oncogene Proteins medicine melanoma Humans Viability assay Physical and Theoretical Chemistry 030304 developmental biology Cell Proliferation benzimidazoles Organic Chemistry Drug Repositioning Fenbendazole medicine.disease High-Throughput Screening Assays Cell culture Cancer research biology.protein Drug Screening Assays Antitumor Tumor Suppressor Protein p53 MdmX |
| Zdroj: | Molecules Volume 24 Issue 11 Molecules, Vol 24, Iss 11, p 2152 (2019) |
| ISSN: | 1420-3049 |
| Popis: | Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53&ndash p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules. In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators. |
| Databáze: | OpenAIRE |
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