2. Academic Validation
  3. Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells

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

  • Eur J Med Chem. 2016 Oct 21:122:611-618. doi: 10.1016/j.ejmech.2016.06.043.
Silvina Grasso 1,  Gustavo J S Pereira 2,  Caroline Palmeira-Dos-Santos 2,  Andrana K Calgarotto 2,  Isabel Martínez-Lacaci 3,  Jose Antonio Ferragut 4,  Soraya S Smaili 5,  Claudia Bincoletto 6
Affiliations

Affiliations

  • 1 Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
  • 2 Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
  • 3 Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain; Unidad AECC de Investigación Traslacional en Cáncer, Hospital Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain.
  • 4 Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain.
  • 5 Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil. Electronic address: soraya.smaili23@gmail.com.
  • 6 Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil. Electronic address: claudia.bincoletto@unifesp.br.
PMID: 27448918 DOI: 10.1016/j.ejmech.2016.06.043
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 μM exerted an arrest in the cell cycle (G1 phase), higher concentrations (10 μM) 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.

Keywords

Apoptosis; Autophagy; CRC cells (SW480 and HT29); Selumetinib (AZD6244).

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