Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/34988 http://dx.doi.org/10.1371/journal.pone.0038698 |
Resumo: | Background: Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. the purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naive mice.Methodology/Principal Findings: the jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). the free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner.Conclusions/Significance: the results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma. |
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Massaoka, Mariana Hiromi [UNIFESP]Matsuo, Alisson Leonardo [UNIFESP]Figueiredo, Carlos Rogerio [UNIFESP]Farias, Camyla F. [UNIFESP]Girola, Natalia [UNIFESP]Arruda, Denise Costa [UNIFESP]Scutti, Jorge Augusto Borin [UNIFESP]Romoff, PauleteFavero, Oriana A.Ferreira, Marcelo J. P.Lago, Joao Henrique Ghilardi [UNIFESP]Travassos, Luiz Rodolpho [UNIFESP]Universidade Federal de São Paulo (UNIFESP)Univ Presbiteriana Mackenzie2016-01-24T14:27:21Z2016-01-24T14:27:21Z2012-06-06Plos One. San Francisco: Public Library Science, v. 7, n. 6, 11 p., 2012.1932-6203http://repositorio.unifesp.br/handle/11600/34988http://dx.doi.org/10.1371/journal.pone.0038698WOS000305348400087.pdf10.1371/journal.pone.0038698WOS:000305348400087Background: Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. the purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naive mice.Methodology/Principal Findings: the jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). the free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner.Conclusions/Significance: the results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Unidade Oncol Expt, São Paulo, BrazilUniv Presbiteriana Mackenzie, Ctr Ciencias & Humanidades, São Paulo, BrazilUniv Presbiteriana Mackenzie, Ctr Ciencias Biol & Saude, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Diadema, SP, BrazilUniversidade Federal de São Paulo, Unidade Oncol Expt, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Diadema, SP, BrazilFAPESP: 2010/51423-0Web of Science11engPublic Library SciencePlos OneJacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivoinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000305348400087.pdfapplication/pdf1508283${dspace.ui.url}/bitstream/11600/34988/1/WOS000305348400087.pdf4f6d22bf00a72f4bbfd6bb14f9de3d68MD51open accessTEXTWOS000305348400087.pdf.txtWOS000305348400087.pdf.txtExtracted texttext/plain62942${dspace.ui.url}/bitstream/11600/34988/9/WOS000305348400087.pdf.txt3dc5cb62d664dc3640f68217efb53536MD59open accessTHUMBNAILWOS000305348400087.pdf.jpgWOS000305348400087.pdf.jpgIM Thumbnailimage/jpeg7853${dspace.ui.url}/bitstream/11600/34988/11/WOS000305348400087.pdf.jpgce9fe532be2b8382236488ce839e164aMD511open access11600/349882023-06-05 19:20:51.989open accessoai:repositorio.unifesp.br:11600/34988Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-06-05T22:20:51Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
title |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
spellingShingle |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo Massaoka, Mariana Hiromi [UNIFESP] |
title_short |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
title_full |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
title_fullStr |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
title_full_unstemmed |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
title_sort |
Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity in Vivo |
author |
Massaoka, Mariana Hiromi [UNIFESP] |
author_facet |
Massaoka, Mariana Hiromi [UNIFESP] Matsuo, Alisson Leonardo [UNIFESP] Figueiredo, Carlos Rogerio [UNIFESP] Farias, Camyla F. [UNIFESP] Girola, Natalia [UNIFESP] Arruda, Denise Costa [UNIFESP] Scutti, Jorge Augusto Borin [UNIFESP] Romoff, Paulete Favero, Oriana A. Ferreira, Marcelo J. P. Lago, Joao Henrique Ghilardi [UNIFESP] Travassos, Luiz Rodolpho [UNIFESP] |
author_role |
author |
author2 |
Matsuo, Alisson Leonardo [UNIFESP] Figueiredo, Carlos Rogerio [UNIFESP] Farias, Camyla F. [UNIFESP] Girola, Natalia [UNIFESP] Arruda, Denise Costa [UNIFESP] Scutti, Jorge Augusto Borin [UNIFESP] Romoff, Paulete Favero, Oriana A. Ferreira, Marcelo J. P. Lago, Joao Henrique Ghilardi [UNIFESP] Travassos, Luiz Rodolpho [UNIFESP] |
author2_role |
author author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Univ Presbiteriana Mackenzie |
dc.contributor.author.fl_str_mv |
Massaoka, Mariana Hiromi [UNIFESP] Matsuo, Alisson Leonardo [UNIFESP] Figueiredo, Carlos Rogerio [UNIFESP] Farias, Camyla F. [UNIFESP] Girola, Natalia [UNIFESP] Arruda, Denise Costa [UNIFESP] Scutti, Jorge Augusto Borin [UNIFESP] Romoff, Paulete Favero, Oriana A. Ferreira, Marcelo J. P. Lago, Joao Henrique Ghilardi [UNIFESP] Travassos, Luiz Rodolpho [UNIFESP] |
description |
Background: Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. the purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naive mice.Methodology/Principal Findings: the jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). the free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner.Conclusions/Significance: the results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma. |
publishDate |
2012 |
dc.date.issued.fl_str_mv |
2012-06-06 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:27:21Z |
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2016-01-24T14:27:21Z |
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article |
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Plos One. San Francisco: Public Library Science, v. 7, n. 6, 11 p., 2012. |
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http://repositorio.unifesp.br/handle/11600/34988 http://dx.doi.org/10.1371/journal.pone.0038698 |
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1932-6203 |
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WOS000305348400087.pdf |
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10.1371/journal.pone.0038698 |
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Plos One. San Francisco: Public Library Science, v. 7, n. 6, 11 p., 2012. 1932-6203 WOS000305348400087.pdf 10.1371/journal.pone.0038698 WOS:000305348400087 |
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http://repositorio.unifesp.br/handle/11600/34988 http://dx.doi.org/10.1371/journal.pone.0038698 |
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