A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC

Abstract Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic...

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Autores principales:	Leleesha Samaraweera, Alfred Adomako, Alicia Rodriguez-Gabin, Hayley M. McDaid
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8bf6e32804f94f5480e8b18e2a01b3ef
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spelling	oai:doaj.org-article:8bf6e32804f94f5480e8b18e2a01b3ef2021-12-02T15:05:10ZA Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC10.1038/s41598-017-01964-12045-2322https://doaj.org/article/8bf6e32804f94f5480e8b18e2a01b3ef2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01964-1https://doaj.org/toc/2045-2322Abstract Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence rather than potentiation of cell death. Senescence occurred following cisplatin- or Taxol-treatment in cell lines from both cancer types and was associated with decreased histone 3 (H3) acetylation and increased Bcl-xL expression: the latter a biomarker of senescence and target of anti-senescence therapeutics, or senolytics. Since H3 acetylation and Bcl-xL expression were altered in senescence, we subsequently evaluated pano as a senolytic in chemotherapy-treated cancer cells enriched for senescent cells. Pano caused cell death at significantly higher rates compared to repeat dosing with chemotherapy. This was associated with decreased expression of Bcl-xL and increased acetylated H3, reversing the expression patterns observed in senescence. These data support evaluating pano as a post-chemotherapy senolytic with the potential to kill persistent senescent cells that accumulate during standard chemotherapy in NSCLC and HNSCC.Leleesha SamaraweeraAlfred AdomakoAlicia Rodriguez-GabinHayley M. McDaidNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leleesha Samaraweera Alfred Adomako Alicia Rodriguez-Gabin Hayley M. McDaid A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
description	Abstract Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence rather than potentiation of cell death. Senescence occurred following cisplatin- or Taxol-treatment in cell lines from both cancer types and was associated with decreased histone 3 (H3) acetylation and increased Bcl-xL expression: the latter a biomarker of senescence and target of anti-senescence therapeutics, or senolytics. Since H3 acetylation and Bcl-xL expression were altered in senescence, we subsequently evaluated pano as a senolytic in chemotherapy-treated cancer cells enriched for senescent cells. Pano caused cell death at significantly higher rates compared to repeat dosing with chemotherapy. This was associated with decreased expression of Bcl-xL and increased acetylated H3, reversing the expression patterns observed in senescence. These data support evaluating pano as a post-chemotherapy senolytic with the potential to kill persistent senescent cells that accumulate during standard chemotherapy in NSCLC and HNSCC.
format	article
author	Leleesha Samaraweera Alfred Adomako Alicia Rodriguez-Gabin Hayley M. McDaid
author_facet	Leleesha Samaraweera Alfred Adomako Alicia Rodriguez-Gabin Hayley M. McDaid
author_sort	Leleesha Samaraweera
title	A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
title_short	A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
title_full	A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
title_fullStr	A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
title_full_unstemmed	A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
title_sort	novel indication for panobinostat as a senolytic drug in nsclc and hnscc
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8bf6e32804f94f5480e8b18e2a01b3ef
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A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC

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