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

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]

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

• 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: 10/15496-3 - Mecanismos moleculares envolvidos no controle da agressividade do câncer de pâncreas por inibidores de proteínas fosfatases
• Beneficiário: Karin Juliane Pelizzaro Rocha
• Modalidade de apoio: 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
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• 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
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• 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
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica