Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/62608 |
Resumo: | The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato<sup>®</sup>), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors. |
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Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell linesgliomacytotoxic activitysemi-synthetic derivativeingenolEuphorbiatirucalliprotein kinase CautophagyScience & TechnologyThe identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato<sup>®</sup>), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors.This research received was funded by Amazonia Fitomedicamentos Ltda, and Barretos Cancer Hospital, all from Brazil.Multidisciplinary Digital Publishing InstituteUniversidade do MinhoSilva, Viviane Aline OliveiraRosa, Marcela NunesTansini, AlineMartinho, OlgaTanuri, AmilcarEvangelista, Adriane FeijóCruvinel Carloni, AdrianaLima, João PauloPianowski, Luiz FranciscoReis, R. M.2019-11-222019-11-22T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/62608engSilva, V.A.O.; Rosa, M.N.; Tansini, A.; Martinho, O.; Tanuri, A.; Evangelista, A.F.; Cruvinel Carloni, A.; Lima, J.P.; Pianowski, L.F.; Reis, R.M. Semi-Synthetic Ingenol Derivative from Euphorbia tirucalli Inhibits Protein Kinase C Isotypes and Promotes Autophagy and S-Phase Arrest on Glioma Cell Lines. Molecules 2019, 24, 4265.1420-304910.3390/molecules2423426531771098https://www.mdpi.com/1420-3049/24/23/4265info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:37:05Zoai:repositorium.sdum.uminho.pt:1822/62608Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:33:20.336600Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
title |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
spellingShingle |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines Silva, Viviane Aline Oliveira glioma cytotoxic activity semi-synthetic derivative ingenol Euphorbiatirucalli protein kinase C autophagy Science & Technology |
title_short |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
title_full |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
title_fullStr |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
title_full_unstemmed |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
title_sort |
Semi-synthetic ingenol derivative from euphorbia tirucalli inhibits protein kinase C isotypes and promotes autophagy and S-phase arrest on glioma cell lines |
author |
Silva, Viviane Aline Oliveira |
author_facet |
Silva, Viviane Aline Oliveira Rosa, Marcela Nunes Tansini, Aline Martinho, Olga Tanuri, Amilcar Evangelista, Adriane Feijó Cruvinel Carloni, Adriana Lima, João Paulo Pianowski, Luiz Francisco Reis, R. M. |
author_role |
author |
author2 |
Rosa, Marcela Nunes Tansini, Aline Martinho, Olga Tanuri, Amilcar Evangelista, Adriane Feijó Cruvinel Carloni, Adriana Lima, João Paulo Pianowski, Luiz Francisco Reis, R. M. |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Silva, Viviane Aline Oliveira Rosa, Marcela Nunes Tansini, Aline Martinho, Olga Tanuri, Amilcar Evangelista, Adriane Feijó Cruvinel Carloni, Adriana Lima, João Paulo Pianowski, Luiz Francisco Reis, R. M. |
dc.subject.por.fl_str_mv |
glioma cytotoxic activity semi-synthetic derivative ingenol Euphorbiatirucalli protein kinase C autophagy Science & Technology |
topic |
glioma cytotoxic activity semi-synthetic derivative ingenol Euphorbiatirucalli protein kinase C autophagy Science & Technology |
description |
The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato<sup>®</sup>), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-11-22 2019-11-22T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/62608 |
url |
http://hdl.handle.net/1822/62608 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Silva, V.A.O.; Rosa, M.N.; Tansini, A.; Martinho, O.; Tanuri, A.; Evangelista, A.F.; Cruvinel Carloni, A.; Lima, J.P.; Pianowski, L.F.; Reis, R.M. Semi-Synthetic Ingenol Derivative from Euphorbia tirucalli Inhibits Protein Kinase C Isotypes and Promotes Autophagy and S-Phase Arrest on Glioma Cell Lines. Molecules 2019, 24, 4265. 1420-3049 10.3390/molecules24234265 31771098 https://www.mdpi.com/1420-3049/24/23/4265 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799132850419662848 |