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Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition

Colorectal cancer (CRC) is the third most prevalent form of cancer in the United States and results in over 50,000 deaths per year. Treatments for metastatic CRC are limited, and therefore there is an unmet clinical need for more effective therapies. In our prior work, we coupled high-throughput che...

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Autores principales: Dayanidhi, Divya L., Somarelli, Jason A., Mantyh, John B., Rupprecht, Gabrielle, Roghani, Roham Salman, Vincoff, Sophia, Shin, Iljin, Zhao, Yiquan, Kim, So Young, McCall, Shannon, Hong, Jiyong, Hsu, David S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894252/
https://www.ncbi.nlm.nih.gov/pubmed/36743670
http://dx.doi.org/10.3389/fmed.2022.999004
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author Dayanidhi, Divya L.
Somarelli, Jason A.
Mantyh, John B.
Rupprecht, Gabrielle
Roghani, Roham Salman
Vincoff, Sophia
Shin, Iljin
Zhao, Yiquan
Kim, So Young
McCall, Shannon
Hong, Jiyong
Hsu, David S.
author_facet Dayanidhi, Divya L.
Somarelli, Jason A.
Mantyh, John B.
Rupprecht, Gabrielle
Roghani, Roham Salman
Vincoff, Sophia
Shin, Iljin
Zhao, Yiquan
Kim, So Young
McCall, Shannon
Hong, Jiyong
Hsu, David S.
author_sort Dayanidhi, Divya L.
collection PubMed
description Colorectal cancer (CRC) is the third most prevalent form of cancer in the United States and results in over 50,000 deaths per year. Treatments for metastatic CRC are limited, and therefore there is an unmet clinical need for more effective therapies. In our prior work, we coupled high-throughput chemical screens with patient-derived models of cancer to identify new potential therapeutic targets for CRC. However, this pipeline is limited by (1) the use of cell lines that do not appropriately recapitulate the tumor microenvironment, and (2) the use of patient-derived xenografts (PDXs), which are time-consuming and costly for validation of drug efficacy. To overcome these limitations, we have turned to patient-derived organoids. Organoids are increasingly being accepted as a “standard” preclinical model that recapitulates tumor microenvironment cross-talk in a rapid, cost-effective platform. In the present work, we employed a library of natural products, intermediates, and drug-like compounds for which full synthesis has been demonstrated. Using this compound library, we performed a high-throughput screen on multiple low-passage cancer cell lines to identify potential treatments. The top candidate, psymberin, was further validated, with a focus on CRC cell lines and organoids. Mechanistic and genomics analyses pinpointed protein translation inhibition as a mechanism of action of psymberin. These findings suggest the potential of psymberin as a novel therapy for the treatment of CRC.
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spelling pubmed-98942522023-02-03 Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition Dayanidhi, Divya L. Somarelli, Jason A. Mantyh, John B. Rupprecht, Gabrielle Roghani, Roham Salman Vincoff, Sophia Shin, Iljin Zhao, Yiquan Kim, So Young McCall, Shannon Hong, Jiyong Hsu, David S. Front Med (Lausanne) Medicine Colorectal cancer (CRC) is the third most prevalent form of cancer in the United States and results in over 50,000 deaths per year. Treatments for metastatic CRC are limited, and therefore there is an unmet clinical need for more effective therapies. In our prior work, we coupled high-throughput chemical screens with patient-derived models of cancer to identify new potential therapeutic targets for CRC. However, this pipeline is limited by (1) the use of cell lines that do not appropriately recapitulate the tumor microenvironment, and (2) the use of patient-derived xenografts (PDXs), which are time-consuming and costly for validation of drug efficacy. To overcome these limitations, we have turned to patient-derived organoids. Organoids are increasingly being accepted as a “standard” preclinical model that recapitulates tumor microenvironment cross-talk in a rapid, cost-effective platform. In the present work, we employed a library of natural products, intermediates, and drug-like compounds for which full synthesis has been demonstrated. Using this compound library, we performed a high-throughput screen on multiple low-passage cancer cell lines to identify potential treatments. The top candidate, psymberin, was further validated, with a focus on CRC cell lines and organoids. Mechanistic and genomics analyses pinpointed protein translation inhibition as a mechanism of action of psymberin. These findings suggest the potential of psymberin as a novel therapy for the treatment of CRC. Frontiers Media S.A. 2022-12-20 /pmc/articles/PMC9894252/ /pubmed/36743670 http://dx.doi.org/10.3389/fmed.2022.999004 Text en Copyright © 2022 Dayanidhi, Somarelli, Mantyh, Rupprecht, Roghani, Vincoff, Shin, Zhao, Kim, McCall, Hong and Hsu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Dayanidhi, Divya L.
Somarelli, Jason A.
Mantyh, John B.
Rupprecht, Gabrielle
Roghani, Roham Salman
Vincoff, Sophia
Shin, Iljin
Zhao, Yiquan
Kim, So Young
McCall, Shannon
Hong, Jiyong
Hsu, David S.
Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
title Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
title_full Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
title_fullStr Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
title_full_unstemmed Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
title_short Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
title_sort psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894252/
https://www.ncbi.nlm.nih.gov/pubmed/36743670
http://dx.doi.org/10.3389/fmed.2022.999004
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