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The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK

The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells...

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Autores principales: Mattos, Daphne R., Wan, Xuemei, Serrill, Jeffrey D., Nguyen, Minh H., Humphreys, Ian R., Viollet, Benoit, Smith, Amos B., McPhail, Kerry L., Ishmael, Jane E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320534/
https://www.ncbi.nlm.nih.gov/pubmed/35877711
http://dx.doi.org/10.3390/md20070418
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author Mattos, Daphne R.
Wan, Xuemei
Serrill, Jeffrey D.
Nguyen, Minh H.
Humphreys, Ian R.
Viollet, Benoit
Smith, Amos B.
McPhail, Kerry L.
Ishmael, Jane E.
author_facet Mattos, Daphne R.
Wan, Xuemei
Serrill, Jeffrey D.
Nguyen, Minh H.
Humphreys, Ian R.
Viollet, Benoit
Smith, Amos B.
McPhail, Kerry L.
Ishmael, Jane E.
author_sort Mattos, Daphne R.
collection PubMed
description The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.
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spelling pubmed-93205342022-07-27 The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK Mattos, Daphne R. Wan, Xuemei Serrill, Jeffrey D. Nguyen, Minh H. Humphreys, Ian R. Viollet, Benoit Smith, Amos B. McPhail, Kerry L. Ishmael, Jane E. Mar Drugs Article The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK. MDPI 2022-06-27 /pmc/articles/PMC9320534/ /pubmed/35877711 http://dx.doi.org/10.3390/md20070418 Text en © 2022 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
Mattos, Daphne R.
Wan, Xuemei
Serrill, Jeffrey D.
Nguyen, Minh H.
Humphreys, Ian R.
Viollet, Benoit
Smith, Amos B.
McPhail, Kerry L.
Ishmael, Jane E.
The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK
title The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK
title_full The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK
title_fullStr The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK
title_full_unstemmed The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK
title_short The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK
title_sort marine-derived macrolactone mandelalide a is an indirect activator of ampk
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320534/
https://www.ncbi.nlm.nih.gov/pubmed/35877711
http://dx.doi.org/10.3390/md20070418
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