Disulfiram – an old antialcoholism drug tackling cancer stem cells to sensitize breast cancer cells to conventional anticancer drugs


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Nga C Yip1, Ivo S Fombon1, Peng Liu1, Sarah Brown1, Vinodh Kaannappan1, Angel L Armesilla1, John L Darling1, James Cassidy2, Weiguang Wang1
1University of Wolverhampton, Wolverhampton, United Kingdom,2University of Glasgow, Glasgow, United Kingdom

Background

Chemoresistance remains the major obstacle for the success of cancer chemotherapy. Cancer stem cells (CSCs) are the main cause of chemoresistance. Conventional anticancer drugs eradicate the bulk cancer cells but spare CSCs population which becomes the ‘seeds’ for cancer relapse. Therefore development of novel CSCs-targeting drugs becomes one of the ‘hot-spots’ in cancer studies and anticancer drug development. Disulfiram (DS), an old antialcoholism drug, is highly toxic to a wide range of cancer types and reverse chemoresistance governed by different mechanisms. DS is also a very strong inhibitor of aldehyde dehydrogenase, a functional CSCs marker. Therefore DS may be a potent novel anti-CSCs agent.

Method

Cytotoxicity, clonogenic and reporter gene assays, CSCs culture, western blot, EMSA, FACS

Results

DS was highly cytotoxic to BC cells in vitro in a copper-dependent manner. In copper (Cu, 1µM) containing medium the IC50 concentrations of DS in BC cell lines were 200 - 500nM. DS/Cu enhanced the cytotoxicity of conventional anti-BC drugs [gemecitabine (dFdC): 1.2 - 4-fold, doxorubicine (DOX): 8 - 11-fold; and paclitaxel (PAC): 4 - 10-fold] in BC cell lines and completely reversed the chemoresistant in dFdC and PAC resistant cell lines. The P-glycoprotein expression in the resistant cell lines were abolished by DS/Cu. CI-isobologram analysis demonstrated synergistic effect between DS and anticancer drugs. Clonogenic assay demonstrated that DS/Cu blocked BC cell re-generating ability. The mammosphere formation and the CSCs population (CD24Low/CD44High) in mammospheric cells were demolished by DS/Cu at a very low concentration (1 µM). DS/Cu simultaneously inhibited NF-?B activity, induced ROS activity and persistently activated JNK and p38 pathways.

Conclusion

  1. DS was cytotoxic and enhanced cytotoxicity of conventional anticancer drugs to BC cell lines.
  2. DS strongly inhibited BC CSCs.
  3. DS simultaneously modulated ROS-MAPK and NF-?B.
  4. Further study may lead to repositioning of DS for cancer therapeutics.