TITLE:
Disulfiram’s Antineoplastic Effects on Ovarian Cancer
AUTHORS:
Youssef A. Rezk, Kun Yang, Shoumei Bai, Karen Mclean, Carolyn Johnston, R. Kevin Reynolds, Ronald J. Buckanovich
KEYWORDS:
Antineoplastic, ALDH, Disulfiram, NSG Mice, Ovarian Cancer Stem Cells
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.6 No.14,
December
11,
2015
ABSTRACT: Objective: Aldehyde dehydrogenase (ALDH) enzymatic activity identifies
ovarian cancer stem-like cells. We investigated the antineoplastic activity of
the ALDH inhibitor Disulfiram on bulk ovarian cancer cells and CD133+/ALDH+ cancer stem-like cells. Study Design: Ovarian cancer cell lines, human ovarian
surface epithelial cells, and mesenchymal stem cells were treated with
increasing concentrations of Disulfiram and/or Cisplatin in vitro. Treated cells were assessed for viability or FACS-analyzed
for either percentage of ovarian cancer stem-like cells or induction of
apoptosis. Disulfiram’s impact on cancer stem-like cells was tested in vitro using tumor sphere formation assays
and in vivo using tumor initiation
assays with in vitro-treated A2780
cells in NSG mice. Finally, Disulfiram’s in
vivo activity was assessed versus CD133+/ALDH+ cell-initiated tumor xenografts. Results: Disulfiram demonstrated
antineoplastic activity against multiple ovarian cancer cell lines. While
Disulfiram had limited in vitro toxicity against human ovarian surface epithelial cells or mesenchymal stem
cells (IC50 of ~15 μM and >30 μM, respectively), its antineoplastic activity
against cell lines was comparable to Cisplatin (IC50 ~1.5 μM).
Disulfiram-mediated cell death was due, at least in part, to induction of
apoptosis. Disulfiram activity was additive with chemotherapy. Disulfiram
demonstrated selective depletion of CD44+ cells but not the CD133+ cancer stem-like cells. Disulfiram had no therapeutic impact on tumor
initiation studies or in vivo therapy
of whole cell line or stem cell-initiated tumor xenografts. Conclusions: In
biologically relevant concentrations, Disulfiram has clear antineoplastic
activity against ovarian cancer cells in
vitro. Disulfiram selectively depleted CD44+ but not CD133+ ovarian cancer stem-like cells in vitro.
However, Disulfiram had no significant activity in vivo. Thus, improved and more selective ALDH inhibitors may be
required to target ovarian cancer stem cells.