Tuomainen, K., Hyytiäinen, A., Al-Samadi, A. et al. High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma. Sci Rep 11, 14755 (2021). https://doi.org/10.1038/s41598-021-94259-5
High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
|Author:||Tuomainen, Katja1,2; Hyytiäinen, Aini1,2; Al-Samadi, Ahmed1,2;|
1Department of Oral and Maxillofacial Diseases, University of Helsinki, 00014, Helsinki, Finland
2Translational Immunology Research Program (TRIMM), University of Helsinki, 00014, Helsinki, Finland
3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290, Helsinki, Finland
4Cancer and Translational Medicine Research Unit, University of Oulu, 90014, Oulu, Finland
5Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital (HUS), University of Helsinki, 00029, Helsinki, Finland
6Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
7Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Karolinska Hospital, 141 86, Stockholm, Sweden
8Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
9Medical Research Center, Oulu University Hospital, 90220, Oulu, Finland
10Department of Pathology, Helsinki University Hospital (HUS), 00029, Helsinki, Finland
|Online Access:||PDF Full Text (PDF, 3.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021101150599
|Publish Date:|| 2021-10-11
Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. Here, we performed a high-throughput compound screen to identify a synergistic interaction between ionizing radiation and 396 anticancer compounds. The assay was run using five human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) cell lines cultured on the human tumor-derived matrix Myogel. Our screen identified several compounds with strong synergistic and antagonistic effects, which we further investigated using multiple irradiation doses. Navitoclax, which emerged as the most promising radiosensitizer, exhibited synergy with irradiation regardless of the p53 mutation status in all 13 HNSCC cell lines. We performed a live cell apoptosis assay for two representative HNSCC cell lines to examine the effects of navitoclax and irradiation. As a single agent, navitoclax reduced proliferation and induced apoptosis in a dose-dependent manner, whereas the navitoclax–irradiation combination arrested cell cycle progression and resulted in substantially elevated apoptosis. Overall, we demonstrated that combining navitoclax with irradiation resulted in synergistic in vitro antitumor effects in HNSCC cell lines, possibly indicating the therapeutic potential for HNSCC patients.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
KT was financially supported by a fellowship from the Doctoral Program in Clinical Research at the University of Helsinki. This project was funded by the Cancer Society of Finland, the Sigrid Juselius Foundation, The Emil Aaltonen Foundation, Cancer Foundation Finland, the Jane and Aatos Erkko Foundation and the Helsinki University Central Hospital research funds.
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