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Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells

Liu, P., Kumar, I., Brown, S., Kannappan, V., Tawari, P., Tang, J., Jiang, Wen Guo, Armesilla, A., Darling, J. and Wang, W. 2013. Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells. British Journal of Cancer 109 (7) , pp. 1876-1885. 10.1038/bjc.2013.534

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Abstract

Background:Triple-negative breast cancer (TNBC) has significantly worse prognosis. Acquired chemoresistance remains the major cause of therapeutic failure of TNBC. In clinic, the relapsed TNBC is commonly pan-resistant to various drugs with completely different resistant mechanisms. Investigation of the mechanisms and development of new drugs to target pan-chemoresistance will potentially improve the therapeutic outcomes of TNBC patients.Methods:In this study, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)-isobologram, western blot, ALDEFLUOR analysis, clonogenic assay and immunocytochemistry were used.Results:The chemoresistant MDA-MB-231 PAC10 cells are highly cross-resistant to paclitaxel (PAC), cisplatin (CDDP), docetaxel and doxorubicin. The MDA-MB-231 PAC10 cells are quiescent with significantly longer doubling time (64.9 vs 31.7 h). This may be caused by high expression of p21 Waf1. The MDA-MB-231 PAC10 cells express high aldehyde dehydrogenase (ALDH) activity and a panel of embryonic stem cell-related proteins, for example, Oct4, Sox2, Nanog and nuclealisation of HIF2α and NF-κBp65. We have previously reported that disulfiram (DS), an antialcoholism drug, targets cancer stem cells (CSCs) and enhances cytotoxicity of anticancer drugs. Disulfiram abolished CSC characters and completely reversed PAC and CDDP resistance in MDA-MB-231 PAC10 cells.Conclusion:Cancer stem cells may be responsible for acquired pan-chemoresistance. As a drug used in clinic, DS may be repurposed as a CSC inhibitor to reverse the acquired pan-chemoresistance.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: acquired resistance; breast cancer; CSCs; disulfiram; paclitaxel; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cisplatin; Disulfiram; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Humans; Neoplastic Stem Cells; Paclitaxel; Receptor Epidermal Growth Factor; Receptors Estrogen; Receptors Progesterone; Taxoids
Publisher: Nature Publishing Group
ISSN: 0007-0920
Last Modified: 04 Jun 2017 08:18
URI: http://orca-mwe.cf.ac.uk/id/eprint/75600

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