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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness

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Autor(es):
Barcelos, Rosimeire Coura [1] ; Pelizzaro-Rocha, Karin Juliane [2] ; Pastre, Julio Cezar [1] ; Dias, Marina Pereira [2] ; Ferreira-Halder, Carmen Verissima [2] ; Aloise Pilli, Rona Ido [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Univ Estadual Campinas, Inst Chem, Dept Organ Chem, BR-13083970 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Inst Biol, Dept Biochem, BR-13083862 Sao Paulo - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 87, p. 745-758, NOV 24 2014.
Citações Web of Science: 11
Resumo

In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 mu M) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxiainducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 mu M). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment. (c) 2014 Elsevier Masson SAS. All rights reserved. (AU)

Processo FAPESP: 10/16990-1 - Síntese e avaliação da atividade citotóxica de gama-diidropironas: análogos de goniotalamina e de abyssinona II
Beneficiário:Júlio Cezar Pastre
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 10/15496-3 - Mecanismos moleculares envolvidos no controle da agressividade do câncer de pâncreas por inibidores de proteínas fosfatases
Beneficiário:Karin Juliane Pelizzaro Rocha
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 09/51602-5 - Biologia química: novos alvos moleculares naturais e sintéticos contra o câncer, estudos estruturais, avaliação biológica e modo de ação
Beneficiário:Ronaldo Aloise Pilli
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 12/24385-6 - Influência de inibidores de proteínas fosfatases na expressão e/ou atividade de proteínas quinases de câncer de pâncreas
Beneficiário:Marina Pereira Dias
Linha de fomento: Bolsas no Brasil - Iniciação Científica