Your browser doesn't support javascript.
loading
Magnolol derivatives as specific and noncytotoxic inhibitors of breast cancer resistance protein (BCRP/ABCG2).
da Silva Zanzarini, Isadora; Henrique Kita, Diogo; Scheiffer, Gustavo; Karoline Dos Santos, Kelly; de Paula Dutra, Julia; Augusto Pastore, Matteo; Gomes de Moraes Rego, Fabiane; Picheth, Geraldo; Ambudkar, Suresh V; Pulvirenti, Luana; Cardullo, Nunzio; Rotuno Moure, Vivian; Muccilli, Vera; Tringali, Corrado; Valdameri, Glaucio.
Afiliação
  • da Silva Zanzarini I; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil.
  • Henrique Kita D; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Scheiffer G; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil.
  • Karoline Dos Santos K; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil.
  • de Paula Dutra J; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil.
  • Augusto Pastore M; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil.
  • Gomes de Moraes Rego F; Department of Clinical Analysis, Federal University of Parana, Curitiba, Brazil.
  • Picheth G; Department of Clinical Analysis, Federal University of Parana, Curitiba, Brazil.
  • Ambudkar SV; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Pulvirenti L; Istituto di Chimica Biomolecolare del Consiglio Nazionale delle Ricerche (ICB-CNR), Catania, Italy.
  • Cardullo N; Department of Chemical Sciences, University of Catania, Catania, Italy.
  • Rotuno Moure V; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil.
  • Muccilli V; Department of Chemical Sciences, University of Catania, Catania, Italy. Electronic address: vera.muccilli@unict.it.
  • Tringali C; Department of Chemical Sciences, University of Catania, Catania, Italy.
  • Valdameri G; Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Brazil. Electronic address: gvaldameri@ufpr.br.
Bioorg Chem ; 146: 107283, 2024 May.
Article em En | MEDLINE | ID: mdl-38513324
ABSTRACT
The breast cancer resistance protein (BCRP/ABCG2) transporter mediates the efflux of numerous antineoplastic drugs, playing a central role in multidrug resistance related to cancer. The absence of successful clinical trials using specific ABCG2 inhibitors reveals the urge to identify new compounds to attend this critical demand. In this work, a series of 13 magnolol derivatives was tested as ABCG2 inhibitors. Only two compounds, derivatives 10 and 11, showed partial and complete ABCG2 inhibitory effect, respectively. This inhibition was selective toward ABCG2, since none of the 13 compounds inhibited neither P-glycoprotein nor MRP1. Both inhibitors (10 and 11) were not transported by ABCG2 and demonstrated a low cytotoxic profile even at high concentrations (up to 100 µM). 11 emerged as the most promising compound of the series, considering the ratio between cytotoxicity (IG50) and ABCG2 inhibition potency (IC50), showing a therapeutic ratio (TR) higher than observed for 10 (10.5 versus 1.6, respectively). This derivative showed a substrate-independent and a mixed type of inhibition. The effect of compound 11 on the ABCG2 ATPase activity and thermostability revealed allosteric protein changes. This compound did not affect the expression levels of ABCG2 and increased the binding of the conformational-sensitive antibody 5D3. A docking study showed that 11 did not share the same binding site with ABCG2 substrate mitoxantrone. Finally, 11 could revert the chemoresistance to SN-38 mediated by ABCG2.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos de Bifenilo / Neoplasias da Mama / Lignanas / Antineoplásicos Limite: Female / Humans Idioma: En Revista: Bioorg Chem Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos de Bifenilo / Neoplasias da Mama / Lignanas / Antineoplásicos Limite: Female / Humans Idioma: En Revista: Bioorg Chem Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos