Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Biochemistry | Cancer Biology | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal Chemistry and Pharmaceutics | Molecular Biology | Oncology
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 microM) and bisindolylmaleimide-I (10 microM). 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.
5-fluorouracil, bisindolylmaleimide-I, chloramidine, drug retention, exosomes, microvesicles, multidrug resistance, peptidylarginine deiminase, prostate cancer
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Copyright © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
DOI of Published Version
Int J Mol Sci. 2017 May 9;18(5). pii: E1007. doi: 10.3390/ijms18051007. Link to article on publisher's site
International journal of molecular sciences
Kosgodage, Uchini S.; Trindade, Rita P.; Thompson, Paul R.; Inal, Jameel M.; and Lange, Sigrun, "Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy" (2017). Open Access Articles. 3156.
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