Withaferin A and Celastrol Overwhelm Proteostasis
Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were sh...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/1/367 |
| _version_ | 1797358661476024320 |
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| author | Nuria Vilaboa Richard Voellmy |
| author_facet | Nuria Vilaboa Richard Voellmy |
| author_sort | Nuria Vilaboa |
| collection | DOAJ |
| description | Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context. |
| first_indexed | 2024-03-08T15:05:16Z |
| format | Article |
| id | doaj.art-5a39a201735a45eaa24915dea51101c8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T15:05:16Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5a39a201735a45eaa24915dea51101c82024-01-10T14:59:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0125136710.3390/ijms25010367Withaferin A and Celastrol Overwhelm ProteostasisNuria Vilaboa0Richard Voellmy1Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, SpainHSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, SwitzerlandWithaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context.https://www.mdpi.com/1422-0067/25/1/367proteostasisprotein unfoldingprotein aggregationWithaferin AcelastrolIHSF |
| spellingShingle | Nuria Vilaboa Richard Voellmy Withaferin A and Celastrol Overwhelm Proteostasis International Journal of Molecular Sciences proteostasis protein unfolding protein aggregation Withaferin A celastrol IHSF |
| title | Withaferin A and Celastrol Overwhelm Proteostasis |
| title_full | Withaferin A and Celastrol Overwhelm Proteostasis |
| title_fullStr | Withaferin A and Celastrol Overwhelm Proteostasis |
| title_full_unstemmed | Withaferin A and Celastrol Overwhelm Proteostasis |
| title_short | Withaferin A and Celastrol Overwhelm Proteostasis |
| title_sort | withaferin a and celastrol overwhelm proteostasis |
| topic | proteostasis protein unfolding protein aggregation Withaferin A celastrol IHSF |
| url | https://www.mdpi.com/1422-0067/25/1/367 |
| work_keys_str_mv | AT nuriavilaboa withaferinaandcelastroloverwhelmproteostasis AT richardvoellmy withaferinaandcelastroloverwhelmproteostasis |