title: Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells.
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-231PAC10 cells are highly cross-resistant to paclitaxel (PAC), cisplatin (CDDP), docetaxel and doxorubicin. The MDA-MB-231PAC10 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-231PAC10 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-231PAC10 cells.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton, Wolverhampton WV1 1LY, UK.
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: I S
authors.initials: IS
authors.lastname: Kumar
authors.forename: S
authors.initials: S
authors.lastname: Brown
authors.forename: V
authors.initials: V
authors.lastname: Kannappan
authors.forename: P E
authors.initials: PE
authors.lastname: Tawari
authors.forename: J Z
authors.initials: JZ
authors.lastname: Tang
authors.forename: W
authors.initials: W
authors.lastname: Jiang
authors.forename: A L
authors.initials: AL
authors.lastname: Armesilla
authors.forename: J L
authors.initials: JL
authors.lastname: Darling
authors.forename: W
authors.initials: W
authors.lastname: Wang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology*; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D066246:ErbB Receptors; D017239:Paclitaxel; D002945:Cisplatin; D004221:Disulfiram