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Int. J. Mol. Sci. 2017, 18(5), 1007; doi:10.3390/ijms18051007

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy

1
Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK
2
University College London School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK
3
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
4
Department of Biomedical Sciences, University of Westminster, 115, New Cavendish Street, London W1W 6UW, UK
*
Authors to whom correspondence should be addressed.
Academic Editor: Thomas Ritter
Received: 22 February 2017 / Revised: 28 April 2017 / Accepted: 3 May 2017 / Published: 9 May 2017
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Abstract

Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. Potential exosome and MV (EMV) biogenesis inhibitors, tested on human prostate cancer (PC3) cells for their capacity to inhibit EMV release, were also tested on PC3 and MCF-7 (breast cancer) cells for improving chemotherapy. Agents inhibiting EMV release most significantly, whilst maintaining cell viability, were chloramidine (Cl-amidine; 50 µM) and bisindolylmaleimide-I (10 µM). Apoptosis mediated by the chemotherapy drug 5-fluorouracil (5-FU) was significantly enhanced in PC3 cells in the presence of both these EMV inhibitors, resulting in a 62% (Cl-amidine + 5-FU) and 59% (bisindolylmaleimide-I + 5-FU) decrease in numbers of viable PC3 cells compared to 5-FU alone after 24 h. For MCF-7 cells, there were similar increased reductions of viable cells compared to 5-FU treatment alone ranging from 67% (Cl-amidine + 5-FU) to 58% (bisindolylmaleimide-I + 5-FU). Using combinatory treatment, the two EMV inhibitors further reduced the number of viable cancer cells tested. Neither inhibitor affected cell viability. Combining selected EMV inhibitors may pose as a novel strategy to enhance the efficacy of chemotherapeutic drug-mediated apoptosis. View Full-Text
Keywords: microvesicles; exosomes; drug retention; prostate cancer; peptidylarginine deiminase; chloramidine; bisindolylmaleimide-I; 5-fluorouracil; multidrug resistance microvesicles; exosomes; drug retention; prostate cancer; peptidylarginine deiminase; chloramidine; bisindolylmaleimide-I; 5-fluorouracil; multidrug resistance
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MDPI and ACS Style

Kosgodage, U.S.; Trindade, R.P.; Thompson, P.R.; Inal, J.M.; Lange, S. Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy. Int. J. Mol. Sci. 2017, 18, 1007.

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