Stem cell and EMT features of HNSCC-lines are reversed by the aldehyde hydrogenase inhibitor Disulfiram (Antabuse®)

Radio-Chemo resistance leading to disease relapse is one major challenge to improve outcome in squamous cell cancer of the head and neck (HNSCC). Cancer Stem Cells (CSC) are increasingly being implicated in therapy-resistance. We have evaluated Disulfiram (DSF) for its efficacy to inhibit CSCs in HNSCC cell lines and its correlation between CSC-features and drug resistance.

Four HNSCC cell lines were used (UM-SCC9, UM-SCC47, UM-SCC11B, UT-SCC33). Cell viability was assessed using MTT and apoptosis assays, ALDH activity was determined by ALDELUOR and FACS-sorting, cell self-renewal by sphere-and colony-formation assay, migration by wound healing.

The ALDHhigh cell population showed resistance to Cisplatin but are sensitive to DSF DSF/Cu2+. DSF and DSF/Cu2+ synergistically enhanced cytotoxicity of Cisplatin in ALDHhigh cells. The levels of three stemness-related nuclear transcription factors (TF), Sox2, Oct3/4 and Nanog, and ALDH expression were higher in SDCs than MDCs. ALDH expression of SDC and mRNA levels of of these TF were significantly decreased after DSF and DSF/Cu2+ treatment. Moreover, DSF and DSF/Cu2+ treatment significantly reduced the capacity for colony- and spheroid- formation and migration (covered area after 18h: control: 84.67%, DSF: 42.35%, DSF/Cu2+: 38.21%).

Our data demonstrate that DSF/Cu2+ that blocks ALDH enzymatic function, is able to inhibit CSC- and EMT-properties in HNSCC-lines. Moreover, DSF treatment enhances cytotoxicity synergistically and thereby may allow perspectively a reduction of cisplatin or increased effectivity of current standard chemo-radiation regimen in HNSCC. Inhibited EMT may lead to a reduction of metastasis formation.

 

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Dr. Wenhao Yao

Univ. HNO-Klinik, Charité CBF,

Hindenburgdamm 30, 12200

Berlin

Email: [e-mail]

Publication History

Publication Date:
23 April 2019 (online)