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

Local control of head and neck squamous cell carcinoma (HNSCC) remains low. 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. Stemness inhibition was measured by sphere- and colony-formation.

Our results showed strong antiproliferative effects of DSF/Cu2+ in HNSCC cells. Combination of cisplatin with DSF/Cu2+ resulted in synergistic growth inhibition in HNSCC cell lines. Combining irradiation with DSF showed significant reduction of colony forming ability and thus reduced stemness. The combination of cisplatin, DSF/Cu2+ and irradiation enhanced in vitro radio-chemo sensitivity by inducing apoptosis (control: 11.35% DSF/Cu2+ 66.1%), ROS-activity (control: 10.7% DSF/Cu2+ 59.4%), and reversing the G2/M phase arrest (control: 53.2% DSF/Cu2+ 26%). A dosage-reduction (CI) of up to 80-fold with equal effectiveness was achieved.

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:
18 April 2018 (online)