Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells
Jazyk angličtina Země Švýcarsko Médium electronic
Typ dokumentu časopisecké články
Grantová podpora
LQ1605
Ministerstvo Školství, Mládeže a Tělovýchovy
MUNI/A/1087/2018
Ministerstvo Školství, Mládeže a Tělovýchovy
PubMed
31181622
PubMed Central
PMC6600429
DOI
10.3390/molecules24112152
PII: molecules24112152
Knihovny.cz E-zdroje
- Klíčová slova
- Mdm2, MdmX, benzimidazoles, drug repurposing, melanoma, p53,
- MeSH
- albendazol farmakologie MeSH
- benzimidazoly farmakologie MeSH
- down regulace MeSH
- fenbendazol farmakologie MeSH
- jaderné proteiny metabolismus MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- melanom farmakoterapie metabolismus MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- proliferace buněk účinky léků MeSH
- proteiny buněčného cyklu MeSH
- protoonkogenní proteiny c-mdm2 metabolismus MeSH
- protoonkogenní proteiny metabolismus MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- rychlé screeningové testy MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- albendazol MeSH
- benzimidazoly MeSH
- fenbendazol MeSH
- jaderné proteiny MeSH
- MDM2 protein, human MeSH Prohlížeč
- MDM4 protein, human MeSH Prohlížeč
- nádorový supresorový protein p53 MeSH
- proteiny buněčného cyklu MeSH
- protoonkogenní proteiny c-mdm2 MeSH
- protoonkogenní proteiny MeSH
- TP53 protein, human MeSH Prohlížeč
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.
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