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Open AccessArticle

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

1
Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A6, 62500 Brno, Czech Republic
2
International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
3
CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics AS CR, v. v. i., 14220 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
Academic Editors: Atanas G. Atanasov, Karel Šmejkal and Elke Heiss
Molecules 2019, 24(11), 2152; https://doi.org/10.3390/molecules24112152
Received: 10 May 2019 / Revised: 29 May 2019 / Accepted: 5 June 2019 / Published: 7 June 2019
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
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. View Full-Text
Keywords: benzimidazoles; drug repurposing; Mdm2; MdmX; melanoma; p53 benzimidazoles; drug repurposing; Mdm2; MdmX; melanoma; p53
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MDPI and ACS Style

Mrkvová, Z.; Uldrijan, S.; Pombinho, A.; Bartůněk, P.; Slaninová, I. Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells. Molecules 2019, 24, 2152.

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