Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells

0522796 - ÚMG 2020 RIV CH eng J - Journal Article
Mrkvova, Z. - Uldrijan, S. - Pombinho, António R. - Bartůněk, Petr - Slaninová, I.
Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells.
Molecules. Roč. 24, č. 11 (2019), č. článku 2152. E-ISSN 1420-3049
Institutional support: RVO:68378050
Keywords : benzimidazoles * drug repurposing * Mdm2 * MdmX * melanoma * p53
OECD category: Biochemistry and molecular biology
Impact factor: 3.267, year: 2019
Method of publishing: Open access
https://www.mdpi.com/1420-3049/24/11/2152

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-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.
Permanent Link: http://hdl.handle.net/11104/0307228