Disulfiram (Antabuse®): potent radio-chemo sensitizer of HNSCC and derived stem cells in-vitro

The unfavorable prognosis of locally advanced and metastatic HNSCC is primarily due to the development of cancer stem cell (CSC) resistance to chemo-radiation therapy.

Study-aim was to investigate the chemo-radio-sensitizing activity of the ALDH inhibitor Disulfiram (DSF) in HNSCC cell lines and CSC.

Four HNSCC cell lines were used (UM-SCC9, UM-SCC47, UM-SCC11B, UT-SCC33). Combined treatments with cisplatin, DSF and irradiation were performed. Possible synergistic effects were calculated by combination index (CI) analyses. Cell viability was assessed using MTT-test and apoptosis-assays while cell cycle and Reactive Oxygen Species (ROS) was evaluated by FACS.

Our results showed strong anti-proliferative effects of DSF and DSF/Cu2+ in HNSCC cell lines. We demonstrated that DSF and DSF/Cu2+ have a dose-dependent and time-dependent cytotoxicity. The combination of Cisplatin with DSF resulted in a synergistic growth inhibition in all four HNSCC cell lines. The combination of Cisplatin, DSF, DSF/Cu2+ and irradiation enhanced in vitro radio-chemo sensitivity by inducing apoptosis (control: 9.82%, DSF: 39.54%), ROS activity (control: 12.9%, DSF: 43.5%), and reversed the G2/M phase arrest (control: 46.7%, DSF: 35.3%). A dosage-reduction (CI) of up to 80-fold with equal effectiveness was achieved.

DSF and DSF/Cu2+ in combination with cisplatin and irradiation enhanced cytotoxic effects and reduces stemness in treated HNSCC cell lines. The results hold promise for future clinical evaluation by repurposing DSF as a radiosensitizer. However, further studies are required to understand the exact mechanism that leads to synergistic cytotoxicity.

Publication History

Publication Date:
23 April 2019 (online)