Cytotoxic effects of disulfiram and synergism with cisplatin on ovarian cancer cells in vitro

Background:

Epithelial ovarian cancer (EOC) therapy is systemic administration of platinum-based thermotherapy after surgery. Unfortunately, cancer cells either intrinsically are, or relatively rapidly become resistant to cisplatin-based chemotherapy, leading to relapse and therapeutic failure. Increase of sensitivity to cisplatin-based chemotherapy or new regimens for antitumor adjuvant treatment are needed.

Purpose:

To explore the anti-cancer activity of disulfiram (DSF), a clinically approved drug used for treatment of alcohol abuse, and its potential mechanisms. To investigate synergistic effects of DSF with cisplatin treatment by computational quantitative assessment in vitro/in silico.

Methods:

Cell lines used were IGROV1, SKOV3, SKOV3IP1. Apoptotic status of cells was determined by flow cytometry with FLUOS-conjugated Annexin-V and propidium iodide staining. Aldehyde dehydrogenase (ALDH) activity was assessed by Aldefluor assay and flow cytometric analysis. Cell viability and proliferation was measured by MTT assay. Analysis of drug combination effects was based on CompuSyn software.

Results: We demonstrated that DSF with or without Cu²⁺ supplement exhibited promising cytotoxicity in ovarian cancer cell lines. DSF inhibited ALDH activity which is associated with many properties of ovarian cancer stem cell phenotypes and increased intracellular ROS levels which typically triggered ovarian cancer cell apoptosis. DSF treatment significantly enhanced cisplatin-induced apoptosis. Quantitative assessment of DSF in combination with cisplatin and/or paclitaxel in vitro showed that DSF yielded superior synergistic effects in two-drug and three-drug combinations.

Conclusions:

DSF is a potential novel anti-cancer agent. Due to its chemosensitizing ability, DSF is very promising to be combined with cisplatin-based chemotherapy to improve the therapeutic outcome.