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Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma

SIMPLE SUMMARY: Ewing sarcoma is a cancer of the bone and soft tissues that affects children and adolescents. Unfortunately, only 20–30% of patients with metastatic Ewing sarcoma survive, necessitating the need to identify new, more effective therapies. We screened natural product extracts from plan...

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Autores principales: Robles, Andrew J., Dai, Wentao, Haldar, Saikat, Ma, Hongyan, Anderson, Victoria M., Overacker, Ross D., Risinger, April L., Loesgen, Sandra, Houghton, Peter J., Cichewicz, Robert H., Mooberry, Susan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699301/
https://www.ncbi.nlm.nih.gov/pubmed/34944795
http://dx.doi.org/10.3390/cancers13246176
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author Robles, Andrew J.
Dai, Wentao
Haldar, Saikat
Ma, Hongyan
Anderson, Victoria M.
Overacker, Ross D.
Risinger, April L.
Loesgen, Sandra
Houghton, Peter J.
Cichewicz, Robert H.
Mooberry, Susan L.
author_facet Robles, Andrew J.
Dai, Wentao
Haldar, Saikat
Ma, Hongyan
Anderson, Victoria M.
Overacker, Ross D.
Risinger, April L.
Loesgen, Sandra
Houghton, Peter J.
Cichewicz, Robert H.
Mooberry, Susan L.
author_sort Robles, Andrew J.
collection PubMed
description SIMPLE SUMMARY: Ewing sarcoma is a cancer of the bone and soft tissues that affects children and adolescents. Unfortunately, only 20–30% of patients with metastatic Ewing sarcoma survive, necessitating the need to identify new, more effective therapies. We screened natural product extracts from plants and fungal cultures to identify compounds with selective cytotoxic activity against Ewing sarcoma cells, which led to the identification of altertoxin II as a compound with highly selective activity against Ewing sarcoma cells. Mechanism of action studies showed that altertoxin II selectively induces DNA damage in Ewing sarcoma cells, but does not bind to DNA. Additionally, we found that altertoxin II has antitumor activity in a mouse model of Ewing sarcoma, suggesting it will be useful as a lead compound to help identify new molecular targets for the development of new Ewing-sarcoma-specific therapies. ABSTRACT: A screening program designed to identify natural products with selective cytotoxic effects against cell lines representing different types of pediatric solid tumors led to the identification of altertoxin II as a highly potent and selective cytotoxin against Ewing sarcoma cell lines. Altertoxin II, but not the related compounds altertoxin I and alteichin, was highly effective against every Ewing sarcoma cell line tested, with an average 25-fold selectivity for these cells as compared to cells representing other pediatric and adult cancers. Mechanism of action studies revealed that altertoxin II causes DNA double-strand breaks, a rapid DNA damage response, and cell cycle accumulation in the S phase. Our studies also demonstrate that the potent effects of altertoxin II are partially dependent on the progression through the cell cycle, because the G(1) arrest initiated by a CDK4/6 inhibitor decreased antiproliferative potency more than 10 times. Importantly, the cell-type-selective DNA-damaging effects of altertoxin II in Ewing sarcoma cells occur independently of its ability to bind directly to DNA. Ultimately, we found that altertoxin II has a dose-dependent in vivo antitumor efficacy against a Ewing sarcoma xenograft, suggesting that it has potential as a therapeutic drug lead and will be useful to identify novel targets for Ewing-sarcoma-specific therapies.
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spelling pubmed-86993012021-12-24 Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma Robles, Andrew J. Dai, Wentao Haldar, Saikat Ma, Hongyan Anderson, Victoria M. Overacker, Ross D. Risinger, April L. Loesgen, Sandra Houghton, Peter J. Cichewicz, Robert H. Mooberry, Susan L. Cancers (Basel) Article SIMPLE SUMMARY: Ewing sarcoma is a cancer of the bone and soft tissues that affects children and adolescents. Unfortunately, only 20–30% of patients with metastatic Ewing sarcoma survive, necessitating the need to identify new, more effective therapies. We screened natural product extracts from plants and fungal cultures to identify compounds with selective cytotoxic activity against Ewing sarcoma cells, which led to the identification of altertoxin II as a compound with highly selective activity against Ewing sarcoma cells. Mechanism of action studies showed that altertoxin II selectively induces DNA damage in Ewing sarcoma cells, but does not bind to DNA. Additionally, we found that altertoxin II has antitumor activity in a mouse model of Ewing sarcoma, suggesting it will be useful as a lead compound to help identify new molecular targets for the development of new Ewing-sarcoma-specific therapies. ABSTRACT: A screening program designed to identify natural products with selective cytotoxic effects against cell lines representing different types of pediatric solid tumors led to the identification of altertoxin II as a highly potent and selective cytotoxin against Ewing sarcoma cell lines. Altertoxin II, but not the related compounds altertoxin I and alteichin, was highly effective against every Ewing sarcoma cell line tested, with an average 25-fold selectivity for these cells as compared to cells representing other pediatric and adult cancers. Mechanism of action studies revealed that altertoxin II causes DNA double-strand breaks, a rapid DNA damage response, and cell cycle accumulation in the S phase. Our studies also demonstrate that the potent effects of altertoxin II are partially dependent on the progression through the cell cycle, because the G(1) arrest initiated by a CDK4/6 inhibitor decreased antiproliferative potency more than 10 times. Importantly, the cell-type-selective DNA-damaging effects of altertoxin II in Ewing sarcoma cells occur independently of its ability to bind directly to DNA. Ultimately, we found that altertoxin II has a dose-dependent in vivo antitumor efficacy against a Ewing sarcoma xenograft, suggesting that it has potential as a therapeutic drug lead and will be useful to identify novel targets for Ewing-sarcoma-specific therapies. MDPI 2021-12-07 /pmc/articles/PMC8699301/ /pubmed/34944795 http://dx.doi.org/10.3390/cancers13246176 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Robles, Andrew J.
Dai, Wentao
Haldar, Saikat
Ma, Hongyan
Anderson, Victoria M.
Overacker, Ross D.
Risinger, April L.
Loesgen, Sandra
Houghton, Peter J.
Cichewicz, Robert H.
Mooberry, Susan L.
Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma
title Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma
title_full Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma
title_fullStr Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma
title_full_unstemmed Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma
title_short Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma
title_sort altertoxin ii, a highly effective and specific compound against ewing sarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699301/
https://www.ncbi.nlm.nih.gov/pubmed/34944795
http://dx.doi.org/10.3390/cancers13246176
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