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

• Published in: British journal of cancer Vol. 109; no. 7; pp. 1876 - 1885
• Main Authors: Liu, P, Kumar, I S, Brown, S, Kannappan, V, Tawari, P E, Tang, J Z, Jiang, W, Armesilla, A L, Darling, J L, Wang, W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2013; Nature Publishing Group
• Subjects: 692/699/67/1059/2326; 692/699/67/1347; 692/699/67/71; 692/700/565/1436; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Cancer Research; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin - pharmacology; Copper; Cytotoxicity; Disulfiram - pharmacology; Doxorubicin - pharmacology; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Drugs; Enzyme Inhibitors - pharmacology; Epidemiology; Female; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical prognosis; Medical research; Medical sciences; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - drug effects; Oncology; Paclitaxel - pharmacology; Receptor, Epidermal Growth Factor - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Stem cells; Taxoids - pharmacology; Tumors; United Kingdom > UK; paclitaxel; breast cancer; disulfiram; acquired resistance; CSCs; Antineoplastic agent; Breast disease; Antialcohol drug; Acquired; Stem cell; Breast cancer; Malignant tumor; Mammary gland diseases; Cancerology; Taxane derivatives; Paclitaxel; Disulfiram; Reversibility; Cross resistance; Target cell; Antimitotic; Tumor cell; Triple negative breast cancer; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.534

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 HIF2 α and NF- κ Bp65. 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.