Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Abstract Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic o...

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Autores principales:	Emily A. Smith, Natasha T. Hill, Tara Gelb, Khalid A. Garman, Ekaterina I. Goncharova, Heidi R. Bokesch, Chang-Kwon Kim, Karen L. Wendt, Robert H. Cichewicz, Kirk R. Gustafson, Isaac Brownell, Curtis J. Henrich
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0ba58604b5d14bf384c1fbeb026e0be3
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spelling	oai:doaj.org-article:0ba58604b5d14bf384c1fbeb026e0be32021-12-02T16:31:50ZIdentification of natural product modulators of Merkel cell carcinoma cell growth and survival10.1038/s41598-021-93097-92045-2322https://doaj.org/article/0ba58604b5d14bf384c1fbeb026e0be32021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93097-9https://doaj.org/toc/2045-2322Abstract Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic options have shown promise in treating MCC, there remains a need for additional therapeutics as well as probes for better understanding MCC. A high-throughput screening campaign was used to assess the ability of > 25,000 synthetic and natural product compounds as well as > 20,000 natural product extracts to affect growth and survival of VN-MCC and VP-MCC cell lines. Sixteen active compounds were identified that have mechanisms of action reported in the literature along with a number of compounds with unknown mechanisms. Screening results with pure compounds suggest a range of potential targets for MCC including DNA damage, inhibition of DNA or protein synthesis, reactive oxygen species, and proteasome inhibition as well as NFκB inhibition while also suggesting the importance of zinc and/or copper binding. Many of the active compounds, particularly some of the natural products, have multiple reported targets suggesting that this strategy might be a particularly fruitful approach. Processing of several active natural product extracts resulted in the identification of additional MCC-active compounds. Based on these results, further investigations focused on natural products sources, particularly of fungal origin, are expected to yield further potentially useful modulators of MCC.Emily A. SmithNatasha T. HillTara GelbKhalid A. GarmanEkaterina I. GoncharovaHeidi R. BokeschChang-Kwon KimKaren L. WendtRobert H. CichewiczKirk R. GustafsonIsaac BrownellCurtis J. HenrichNature 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 Emily A. Smith Natasha T. Hill Tara Gelb Khalid A. Garman Ekaterina I. Goncharova Heidi R. Bokesch Chang-Kwon Kim Karen L. Wendt Robert H. Cichewicz Kirk R. Gustafson Isaac Brownell Curtis J. Henrich Identification of natural product modulators of Merkel cell carcinoma cell growth and survival
description	Abstract Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic options have shown promise in treating MCC, there remains a need for additional therapeutics as well as probes for better understanding MCC. A high-throughput screening campaign was used to assess the ability of > 25,000 synthetic and natural product compounds as well as > 20,000 natural product extracts to affect growth and survival of VN-MCC and VP-MCC cell lines. Sixteen active compounds were identified that have mechanisms of action reported in the literature along with a number of compounds with unknown mechanisms. Screening results with pure compounds suggest a range of potential targets for MCC including DNA damage, inhibition of DNA or protein synthesis, reactive oxygen species, and proteasome inhibition as well as NFκB inhibition while also suggesting the importance of zinc and/or copper binding. Many of the active compounds, particularly some of the natural products, have multiple reported targets suggesting that this strategy might be a particularly fruitful approach. Processing of several active natural product extracts resulted in the identification of additional MCC-active compounds. Based on these results, further investigations focused on natural products sources, particularly of fungal origin, are expected to yield further potentially useful modulators of MCC.
format	article
author	Emily A. Smith Natasha T. Hill Tara Gelb Khalid A. Garman Ekaterina I. Goncharova Heidi R. Bokesch Chang-Kwon Kim Karen L. Wendt Robert H. Cichewicz Kirk R. Gustafson Isaac Brownell Curtis J. Henrich
author_facet	Emily A. Smith Natasha T. Hill Tara Gelb Khalid A. Garman Ekaterina I. Goncharova Heidi R. Bokesch Chang-Kwon Kim Karen L. Wendt Robert H. Cichewicz Kirk R. Gustafson Isaac Brownell Curtis J. Henrich
author_sort	Emily A. Smith
title	Identification of natural product modulators of Merkel cell carcinoma cell growth and survival
title_short	Identification of natural product modulators of Merkel cell carcinoma cell growth and survival
title_full	Identification of natural product modulators of Merkel cell carcinoma cell growth and survival
title_fullStr	Identification of natural product modulators of Merkel cell carcinoma cell growth and survival
title_full_unstemmed	Identification of natural product modulators of Merkel cell carcinoma cell growth and survival
title_sort	identification of natural product modulators of merkel cell carcinoma cell growth and survival
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0ba58604b5d14bf384c1fbeb026e0be3
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Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

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