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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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]
Total Authors: 6
Affiliation:
[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
Total Affiliations: 2
Document type: Journal article
Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 87, p. 745-758, NOV 24 2014.
Web of Science Citations: 11
Abstract

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)

FAPESP's process: 10/15496-3 - Molecular mechanisms involved in the control of pancreatic cancer aggressiveness by protein phosphatases inhibitors
Grantee:Karin Juliane Pelizzaro Rocha
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 09/51602-5 - Chemical biology: new natural and synthetic molecular targets against cancer, structural studies, biological evaluation and mode of action
Grantee:Ronaldo Aloise Pilli
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 10/16990-1 - Synthesis and evaluation of cytotoxic activity of gama-dihydropyrones: goniothalamin and abyssinone II analogues
Grantee:Júlio Cezar Pastre
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 12/24385-6 - Influence of protein phosphatases inhibitors in the expression and / or activity of protein kinases in pancreatic cancer
Grantee:Marina Pereira Dias
Support Opportunities: Scholarships in Brazil - Scientific Initiation