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Παρασκευή 15 Ιουνίου 2018

Enhanced anticancer effect of MAP30–S3 by cyclosproin A through endosomal escape

Cyclosporin A (CsA) is a calcium antagonist and can enhance the efficacy of some protein drugs, but its mechanism remains unknown. In this study, MAP30, a ribosome-inactivating protein reported to have apoptotic effects on cancer cells, was fused with S3, an epidermal growth factor receptor (EGFR)-targeting peptide. In addition, CsA was used to investigate whether it can further promote the apoptotic effects of S3 fused MAP30 (MAP30–S3). Our result showed that the internalization of FITC-labeled MAP30–S3 was increased significantly by S3 in HeLa cells. Unexpectedly, MAP30–S3 only showed a minor decrease in the viability of EGFR-overexpressing cancer cells, including HeLa, SMMC-7721, and MGC803 (IC50>5 μmol/l). However, 2 μmol/l CsA significantly increased the cytotoxicity of MAP30–S3, especially for HeLa cells (IC50=40.3 nmol/l). In comparison, CsA did not further decrease the cytotoxicity of MAP30–S3 on MRC-5, an EGFR low-expressing cell line from normal lung tissue, indicating that CsA did not affect the cancer-targeting specificity of MAP30–S3. Our results also showed that CsA further increased the apoptotic activity of MAP30–S3 in HeLa cells. CsA could promote the endosomal escape of FITC-MAP30–S3 with a diffused pattern in the cytoplasm. Five endocytic inhibitors were used to investigate the cellular uptake mechanism of MAP30–S3, and the results showed that the endosomal escape-enhancing effect of CsA on MAP30–S3 may be associated with the clathrin-dependent endocytic pathways. Our study suggested that CsA could be a novel endosomal escape enhancer to potentiate the intracellular release of anticancer protein drugs, resulting in their improved therapeutic efficacy. Correspondence to Jian Zhao, PhD, Department of Applied Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China Tel: +86 216 425 2256; fax: +86 216 425 2255; e-mail: zhaojian@ecust.edu.cn or Correspondence to Fu-Jun Wang, MSc, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China Tel: +86 215 132 2515; fax: +86 215 132 2508; e-mail: wfj@shutcm.edu.cn Received January 10, 2018 Accepted April 27, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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