Abstract
Abstract Objective: Disulfiram (DSF), which is used to treat alcohol dependence, has been reported to have anticancer effects in various malignant tumors. However, the anticancer effects and mechanism of DSF in head and neck squamous cell carcinoma (HNSCC) have not yet been studied. In this study, we investigated the anticancer effects and mechanism of DSF in HNSCC. Materials and Methods: Head and neck squamous carcinoma cell lines (FaDu and Hep2) were used to analyze the anticancer effects of DSF. The anticancer effects of DSF were confirmed in vivo using a FaDu xenograft tumor model. Results: The anticancer effects of DSF in HNSCC were found to be copper (Cu) dependent. Specifically, DSF/Cu markedly inhibited HNSCC at a concentration of 1 μM, and their combined inhibitory effect was dose-dependent. After DSF/Cu administration, production of reactive oxygen species (ROS) was remarkable starting at 0.5 μM, suggesting that the inhibitory effects of DSF/Cu on HNSCC are mediated through the formation of ROS. In the HNSCC cell lines, levels of phospho-JNK, phospho-cJun and phospho-p38 were increased after DSF/Cu treatment while levels of phospho-Akt were decreased. These results suggested that the inhibitory effects of DSF/Cu on HNSCC cells involve ROS formation and downregulation of Akt-signaling. Through these molecular mechanisms, DSF ultimately induces the inhibitory effects on HNSCC cell lines mainly through autophagic cell death, not apoptotic cell death. Lastly, we investigated the clinical relevance of DSF/Cu using a HNSCC xenograft animal model, which showed that tumor growth was remarkably decreased by DSF (50 mg/kg injection). Conclusion: Treating patients with both HNSCC and alcohol dependence with DSF may contribute to improved patient survival. The anticancer effects of DSF on HNSCC may suggest new therapeutic potential for this medication in HNSCC patients. Citation Format: Young Min Park, Da Hee Kim, Min Seok Kang, Yoon Woo Koh, Eun Chang Choi, Se-Heon Kim. Anticancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B25.
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