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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Zuzana MrkvováIva Slaninová

Abstract

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 o...Continue Reading

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Citations

Oct 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dongdong WangAtanas G Atanasov
Sep 17, 2020·Cell Death & Disease·Monika StetkovaStjepan Uldrijan
Sep 9, 2020·Immune Network·Deok-Soo SonSamuel E Adunyah

Related Concepts

MDM4 protein, human
TP53 protein, human
MDM2 protein, human
Benzimidazoles
Cell Survival
Dye Exclusion Assays, Antitumor
Panacur
Melanoma
Nucleolar Proteins
Proto-Oncogene Proteins

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