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

J 2019

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

MRKVOVÁ, Zuzana, Stjepan ULDRIJAN, Antonio POMBINHO, Petr BARTUNEK, Iva SLANINOVÁ et. al.

Základní údaje

Originální název

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

Autoři

MRKVOVÁ, Zuzana (203 Česká republika, domácí), Stjepan ULDRIJAN (203 Česká republika, domácí), Antonio POMBINHO (203 Česká republika), Petr BARTUNEK (203 Česká republika) a Iva SLANINOVÁ (203 Česká republika, garant, domácí)

Vydání

Molecules, BASEL, Mayer und Muller, 2019, 1420-3049

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Švýcarsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.267

Kód RIV

RIV/00216224:14110/19:00112405

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.3390/molecules24112152

UT WoS

000472631000125

Klíčová slova anglicky

benzimidazoles; drug repurposing; Mdm2; MdmX; melanoma; p53

Štítky

14110513, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 15. 1. 2020 13:37, Mgr. Tereza Miškechová

Anotace

V originále

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.

Návaznosti

MUNI/A/1087/2018, interní kód MU

Název: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masarykova univerzita, Molekulární a buněčná biologie pro biomedicínské vědy, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

Citovat

MRKVOVÁ, Zuzana, Stjepan ULDRIJAN, Antonio POMBINHO, Petr BARTUNEK a Iva SLANINOVÁ. Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells. Molecules. BASEL: Mayer und Muller, 2019, roč. 24, č. 11, s. 1-14. ISSN 1420-3049. Dostupné z: https://dx.doi.org/10.3390/molecules24112152.

@article{1604477,
   author = {Mrkvová, Zuzana and Uldrijan, Stjepan and Pombinho, Antonio and Bartunek, Petr and Slaninová, Iva},
   article_location = {BASEL},
   article_number = {11},
   doi = {http://dx.doi.org/10.3390/molecules24112152},
   keywords = {benzimidazoles; drug repurposing; Mdm2; MdmX; melanoma; p53},
   language = {eng},
   issn = {1420-3049},
   journal = {Molecules},
   title = {Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells},
   url = {http://dx.doi.org/10.3390/molecules24112152},
   volume = {24},
   year = {2019}
}

TY  - JOUR
ID  - 1604477
AU  - Mrkvová, Zuzana - Uldrijan, Stjepan - Pombinho, Antonio - Bartunek, Petr - Slaninová, Iva
PY  - 2019
TI  - Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells
JF  - Molecules
VL  - 24
IS  - 11
SP  - 1-14
EP  - 1-14
PB  - Mayer und Muller
SN  - 14203049
KW  - benzimidazoles
KW  - drug repurposing
KW  - Mdm2
KW  - MdmX
KW  - melanoma
KW  - p53
UR  - http://dx.doi.org/10.3390/molecules24112152
L2  - http://dx.doi.org/10.3390/molecules24112152
N2  - 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.
ER  -

MRKVOVÁ, Zuzana, Stjepan ULDRIJAN, Antonio POMBINHO, Petr BARTUNEK a Iva SLANINOVÁ. Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells. \textit{Molecules}. BASEL: Mayer und Muller, 2019, roč.~24, č.~11, s.~1-14. ISSN~1420-3049. Dostupné z: https://dx.doi.org/10.3390/molecules24112152.

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