Cargando…
A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma
Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295897/ https://www.ncbi.nlm.nih.gov/pubmed/37371806 http://dx.doi.org/10.3390/biomedicines11061711 |
_version_ | 1785063529933438976 |
---|---|
author | Wermelinger, Guilherme Freimann Rubini, Lucas da Fonseca, Anna Carolina Carvalho Ouverney, Gabriel de Oliveira, Rafael P. R. F. de Souza, Acácio S. Forezi, Luana S. M. Limaverde-Sousa, Gabriel Pinheiro, Sergio Robbs, Bruno Kaufmann |
author_facet | Wermelinger, Guilherme Freimann Rubini, Lucas da Fonseca, Anna Carolina Carvalho Ouverney, Gabriel de Oliveira, Rafael P. R. F. de Souza, Acácio S. Forezi, Luana S. M. Limaverde-Sousa, Gabriel Pinheiro, Sergio Robbs, Bruno Kaufmann |
author_sort | Wermelinger, Guilherme Freimann |
collection | PubMed |
description | Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers. |
format | Online Article Text |
id | pubmed-10295897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102958972023-06-28 A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma Wermelinger, Guilherme Freimann Rubini, Lucas da Fonseca, Anna Carolina Carvalho Ouverney, Gabriel de Oliveira, Rafael P. R. F. de Souza, Acácio S. Forezi, Luana S. M. Limaverde-Sousa, Gabriel Pinheiro, Sergio Robbs, Bruno Kaufmann Biomedicines Article Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers. MDPI 2023-06-14 /pmc/articles/PMC10295897/ /pubmed/37371806 http://dx.doi.org/10.3390/biomedicines11061711 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wermelinger, Guilherme Freimann Rubini, Lucas da Fonseca, Anna Carolina Carvalho Ouverney, Gabriel de Oliveira, Rafael P. R. F. de Souza, Acácio S. Forezi, Luana S. M. Limaverde-Sousa, Gabriel Pinheiro, Sergio Robbs, Bruno Kaufmann A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma |
title | A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma |
title_full | A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma |
title_fullStr | A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma |
title_full_unstemmed | A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma |
title_short | A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma |
title_sort | novel mdm2-binding chalcone induces apoptosis of oral squamous cell carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295897/ https://www.ncbi.nlm.nih.gov/pubmed/37371806 http://dx.doi.org/10.3390/biomedicines11061711 |
work_keys_str_mv | AT wermelingerguilhermefreimann anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT rubinilucas anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT dafonsecaannacarolinacarvalho anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT ouverneygabriel anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT deoliveirarafaelprf anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT desouzaacacios anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT foreziluanasm anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT limaverdesousagabriel anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT pinheirosergio anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT robbsbrunokaufmann anovelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT wermelingerguilhermefreimann novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT rubinilucas novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT dafonsecaannacarolinacarvalho novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT ouverneygabriel novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT deoliveirarafaelprf novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT desouzaacacios novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT foreziluanasm novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT limaverdesousagabriel novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT pinheirosergio novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma AT robbsbrunokaufmann novelmdm2bindingchalconeinducesapoptosisoforalsquamouscellcarcinoma |