Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells

Full text
Author(s):
Grasso, Silvina ; Pereira, Gustavo J. S. ; Palmeira-dos-Santos, Caroline ; Calgarotto, Andrana K. ; Martinez-Lacaci, Isabel ; Antonio Ferragut, Jose ; Smaili, Soraya S. ; Bincoletto, Claudia
Total Authors: 8
Document type: Journal article
Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 122, p. 611-618, OCT 21 2016.
Web of Science Citations: 3
Abstract

Objective: As Selumetinib is a MEK1/2 inhibitor that has gained interest as an anti-tumor agent, the present study was designed to investigate autophagy involvement on Selumetinib-induced apoptosis in colorectal cancer (CRC) cells. Methods: CRC cells death and cycle studies were assessed by AnnexinV-FITC and PI staining, respectively. Autophagy flux was analysed by Western Blot (LC3II and p62 protein levels) and retroviral infection of SW480 cells for siBecn1 RNA interference experiments. Confocal microscopy was used to determine mCherry-EGFP-LC3 distribution. Key findings: The Selumetinib effects were concentration-dependent in SW480 cell line. Whereas 1 mu M exerted an arrest in the cell cycle (G1 phase), higher concentrations (10 mu M) induced cell death, which was accompanied by autophagy blockage in its last stages. Autophagy induction by Rapamycin (RAPA) increased cell survival, whereas pharmacology autophagy inhibition by Bafilomycin A1 (BAF), Chloroquine (CQ) or 3-Methyladenine (3-MA) increased Selumetinib-induced CRC cells death. Conclusions: Altogether, these results suggest that autophagy plays a fundamental role in CRC cells response to Selumetinib. In addition, the combination of Selumetinib with autophagy inhibitors may be a useful therapeutic strategy to enhance its activity against colorectal tumours. (C) 2016 Elsevier Masson SAS. All rights reserved. (AU)

FAPESP's process: 12/51215-4 - Autophagy and glycogen synthase kinase-3 (GSK3) as molecular targets capable of increasing the activity of drugs used in the treatment of myeloid leukemias (acute and chronic)
Grantee:Claudia Bincoletto Trindade
Support Opportunities: Regular Research Grants