Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

Research output: Contribution to journalArticle

Authors

  • Kate Butcher
  • Vinodh Kannappan
  • Rajagopal Sharada Kilari
  • Mark R Morris
  • Angel L Armesilla
  • Weiguang Wang

Colleges, School and Institutes

External organisations

  • Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfrana Street, Wolverhampton WV1 1LY, UK
  • School of Pharmacy, University of Birmingham , Birmingham, B15 2TT, U.K.
  • Faculty of Science & Engineering, University of Wolverhampton, Wolverhampton, WV1 1LY, UK. w.wang2@wlv.ac.uk.

Abstract

BACKGROUND: Disulfiram (DS), an antialcoholism medicine, demonstrated strong anticancer activity in the laboratory but did not show promising results in clinical trials. The anticancer activity of DS is copper dependent. The reaction of DS and copper generates reactive oxygen species (ROS). After oral administration in the clinic, DS is enriched and quickly metabolised in the liver. The associated change of chemical structure may make the metabolites of DS lose its copper-chelating ability and disable their anticancer activity. The anticancer chemical structure of DS is still largely unknown. Elucidation of the relationship between the key chemical structure of DS and its anticancer activity will enable us to modify DS and speed its translation into cancer therapeutics.

METHODS: The cytotoxicity, extracellular ROS activity, apoptotic effect of DS, DDC and their analogues on cancer cells and cancer stem cells were examined in vitro by MTT assay, western blot, extracellular ROS assay and sphere-reforming assay.

RESULTS: Intact thiol groups are essential for the in vitro cytotoxicity of DS. S-methylated diethyldithiocarbamate (S-Me-DDC), one of the major metabolites of DS in liver, completely lost its in vitro anticancer activity. In vitro cytotoxicity of DS was also abolished when its thiuram structure was destroyed. In contrast, modification of the ethyl groups in DS had no significant influence on its anticancer activity.

CONCLUSIONS: The thiol groups and thiuram structure are indispensable for the anticancer activity of DS. The liver enrichment and metabolism may be the major obstruction for application of DS in cancer treatment. A delivery system to protect the thiol groups and development of novel soluble copper-DDC compound may pave the path for translation of DS into cancer therapeutics.

Details

Original languageEnglish
Pages (from-to)753
JournalBMC Cancer
Volume18
Issue number1
Publication statusPublished - 21 Jul 2018