High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma

Abstract 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 s...

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Autores principales:	Katja Tuomainen, Aini Hyytiäinen, Ahmed Al-Samadi, Philipp Ianevski, Aleksandr Ianevski, Swapnil Potdar, Laura Turunen, Jani Saarela, Sergey Kuznetsov, Wafa Wahbi, Maija Risteli, Antti Mäkitie, Outi Monni, Tuula Salo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/94f7ab850a6441f089e9e315a0b84667
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spelling	oai:doaj.org-article:94f7ab850a6441f089e9e315a0b846672021-12-02T16:26:37ZHigh-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma10.1038/s41598-021-94259-52045-2322https://doaj.org/article/94f7ab850a6441f089e9e315a0b846672021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94259-5https://doaj.org/toc/2045-2322Abstract 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.Katja TuomainenAini HyytiäinenAhmed Al-SamadiPhilipp IanevskiAleksandr IanevskiSwapnil PotdarLaura TurunenJani SaarelaSergey KuznetsovWafa WahbiMaija RisteliAntti MäkitieOuti MonniTuula SaloNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katja Tuomainen Aini Hyytiäinen Ahmed Al-Samadi Philipp Ianevski Aleksandr Ianevski Swapnil Potdar Laura Turunen Jani Saarela Sergey Kuznetsov Wafa Wahbi Maija Risteli Antti Mäkitie Outi Monni Tuula Salo High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
description	Abstract 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.
format	article
author	Katja Tuomainen Aini Hyytiäinen Ahmed Al-Samadi Philipp Ianevski Aleksandr Ianevski Swapnil Potdar Laura Turunen Jani Saarela Sergey Kuznetsov Wafa Wahbi Maija Risteli Antti Mäkitie Outi Monni Tuula Salo
author_facet	Katja Tuomainen Aini Hyytiäinen Ahmed Al-Samadi Philipp Ianevski Aleksandr Ianevski Swapnil Potdar Laura Turunen Jani Saarela Sergey Kuznetsov Wafa Wahbi Maija Risteli Antti Mäkitie Outi Monni Tuula Salo
author_sort	Katja Tuomainen
title	High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
title_short	High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
title_full	High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
title_fullStr	High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
title_full_unstemmed	High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
title_sort	high-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for hpv-negative head and neck squamous cell carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/94f7ab850a6441f089e9e315a0b84667
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High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma

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