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

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

Author Grasso, Silvina Autor UNIFESP Google Scholar
Pereira, Gustavo José da Silva Autor UNIFESP Google Scholar
Santos, Caroline Palmeira dos Autor UNIFESP Google Scholar
Calgarotto, Andrana Karla Autor UNIFESP Google Scholar
Martinez-Lacaci, Isabel Google Scholar
Antonio Ferragut, Jose Google Scholar
Smaili, Soraya Soubhi Autor UNIFESP Google Scholar
Bincoletto, Claudia Autor UNIFESP Google Scholar
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.
Keywords Apoptosis
Autophagy
Selumetinib (AZD6244)
CRC cells (SW480 and HT29)
xmlui.dri2xhtml.METS-1.0.item-coverage Paris
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 12/51215-4
Date 2016
Published in European Journal Of Medicinal Chemistry. Paris, v. 122, p. 611-618, 2016.
ISSN 0223-5234 (Sherpa/Romeo, impact factor)
Publisher Elsevier France-Editions Scientifiques Medicales Elsevier
Extent 611-618
Origin http://dx.doi.org/10.1016/j.ejmech.2016.06.043
Access rights Closed access
Type Article
Web of Science ID WOS:000383003900052
URI https://repositorio.unifesp.br/handle/11600/56888

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