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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.
Highlights
Many solid tumors contain a population of cells, termed cancer stem-like cells (CSC)
Using MTT assays, Disulfiram demonstrated an antineoplastic activity against a variety of ovarian cancer cell lines (Figure 1(a) & Figure 1(b)), but was most effective in the platinum-sensitive (A2780, IC50: ~1.5 μM) as opposed to the platinum-resistant (SKOV3, IC50: ~40 μM) cell lines
We compared the cytotoxicity of Disulfiram to that of Cisplatin, and found that the antineoplastic activity of the two drugs in the A2780 cell line is comparable (Cisplatin IC50: ~3 μM, Figure 1(b))
Summary
Many solid tumors contain a population of cells, termed cancer stem-like cells (CSC). CSC, despite constituting a small percentage of the overall cancer cell population, have increased tumor-initiation capacity and have been proposed as a source of disease recurrence [1]. Aldehyde dehydrogenase enzymatic activity (ALDH) has been identified as a marker of CSC in numerous malignancies, including ovarian cancer [2] [3]. ALDH-high (ALDH+) epithelial ovarian cancer cells are chemotherapy-resistant; can both initiate and propagate tumors in mice, and can create heterogeneous lineages of ovarian cancer cells [3]. They meet the American Association for Cancer Research consensus criteria for CSC [4]. We have shown that ALDH and CD133 identify an ovarian cancer differentiation hierarchy [5]
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