Mitochondrial permeability transition induced by the anticancer drug etoposide
Autor(a) principal: | |
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Data de Publicação: | 2001 |
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/10316/5799 https://doi.org/10.1016/S0887-2333(01)00019-4 |
Resumo: | Etoposide (VP-16) is widely used for the treatment of several forms of cancer. The cytotoxicity of VP-16 has been assigned to the induction of apoptotic cell death but the signaling pathway for VP-16-induced apoptosis is essentially unknown. There is some evidence that this process depends on events associated with the loss of mitochondrial membrane potential ([Delta][Psi]) and/or release of apoptogenic factors, putatively as a consequence of mitochondrial permeability transition (MPT) induction. This work evaluates the interference of VP-16 with MPT in vitro, which is characterized by the Ca2+-dependent depolarization of [Delta][Psi], the release of matrix Ca2+ and by extensive swelling of mitochondria. [Delta][Psi] depolarization and Ca2+ release were measured with ion-selective electrodes, and mitochondrial swelling was monitored spectrophotometrically. Incubation of rat liver mitochondria with VP-16 results in a concentration-dependent induction of MPT, evidenced by an increased sensitivity to Ca2+-induced swelling, depolarization of [Delta][Psi], Ca2+ release by mitochondria and stimulation of state 4 oxygen consumption. All of these effects are prevented by preincubating the mitochondria with cyclosporine A, a potent and specific inhibitor of the MPT. Therefore, VP-16 increases the sensitivity of isolated mitochondria to the Ca2+-dependent induction of the MPT. Together, these data provide a possible mechanistic explanation for the previously reported effects of VP-16 on apoptosis induction. |
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Mitochondrial permeability transition induced by the anticancer drug etoposideEtoposideAnticancerApoptosisLiver mitochondriaMitochondrial permeability transitionEtoposide (VP-16) is widely used for the treatment of several forms of cancer. The cytotoxicity of VP-16 has been assigned to the induction of apoptotic cell death but the signaling pathway for VP-16-induced apoptosis is essentially unknown. There is some evidence that this process depends on events associated with the loss of mitochondrial membrane potential ([Delta][Psi]) and/or release of apoptogenic factors, putatively as a consequence of mitochondrial permeability transition (MPT) induction. This work evaluates the interference of VP-16 with MPT in vitro, which is characterized by the Ca2+-dependent depolarization of [Delta][Psi], the release of matrix Ca2+ and by extensive swelling of mitochondria. [Delta][Psi] depolarization and Ca2+ release were measured with ion-selective electrodes, and mitochondrial swelling was monitored spectrophotometrically. Incubation of rat liver mitochondria with VP-16 results in a concentration-dependent induction of MPT, evidenced by an increased sensitivity to Ca2+-induced swelling, depolarization of [Delta][Psi], Ca2+ release by mitochondria and stimulation of state 4 oxygen consumption. All of these effects are prevented by preincubating the mitochondria with cyclosporine A, a potent and specific inhibitor of the MPT. Therefore, VP-16 increases the sensitivity of isolated mitochondria to the Ca2+-dependent induction of the MPT. Together, these data provide a possible mechanistic explanation for the previously reported effects of VP-16 on apoptosis induction.http://www.sciencedirect.com/science/article/B6TCP-440BK3X-3/1/13f3c58c1e8437ebdd53d792afd78b912001info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5799http://hdl.handle.net/10316/5799https://doi.org/10.1016/S0887-2333(01)00019-4engToxicology in Vitro. 15:4-5 (2001) 265-270Custódio, J. B. A.Cardoso, C. M. P.Madeira, V. M. C.Almeida, L. M.info: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:RCAAP2021-09-22T11:40:37Zoai:estudogeral.uc.pt:10316/5799Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:18.712842Repositório 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 |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
title |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
spellingShingle |
Mitochondrial permeability transition induced by the anticancer drug etoposide Custódio, J. B. A. Etoposide Anticancer Apoptosis Liver mitochondria Mitochondrial permeability transition |
title_short |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
title_full |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
title_fullStr |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
title_full_unstemmed |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
title_sort |
Mitochondrial permeability transition induced by the anticancer drug etoposide |
author |
Custódio, J. B. A. |
author_facet |
Custódio, J. B. A. Cardoso, C. M. P. Madeira, V. M. C. Almeida, L. M. |
author_role |
author |
author2 |
Cardoso, C. M. P. Madeira, V. M. C. Almeida, L. M. |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Custódio, J. B. A. Cardoso, C. M. P. Madeira, V. M. C. Almeida, L. M. |
dc.subject.por.fl_str_mv |
Etoposide Anticancer Apoptosis Liver mitochondria Mitochondrial permeability transition |
topic |
Etoposide Anticancer Apoptosis Liver mitochondria Mitochondrial permeability transition |
description |
Etoposide (VP-16) is widely used for the treatment of several forms of cancer. The cytotoxicity of VP-16 has been assigned to the induction of apoptotic cell death but the signaling pathway for VP-16-induced apoptosis is essentially unknown. There is some evidence that this process depends on events associated with the loss of mitochondrial membrane potential ([Delta][Psi]) and/or release of apoptogenic factors, putatively as a consequence of mitochondrial permeability transition (MPT) induction. This work evaluates the interference of VP-16 with MPT in vitro, which is characterized by the Ca2+-dependent depolarization of [Delta][Psi], the release of matrix Ca2+ and by extensive swelling of mitochondria. [Delta][Psi] depolarization and Ca2+ release were measured with ion-selective electrodes, and mitochondrial swelling was monitored spectrophotometrically. Incubation of rat liver mitochondria with VP-16 results in a concentration-dependent induction of MPT, evidenced by an increased sensitivity to Ca2+-induced swelling, depolarization of [Delta][Psi], Ca2+ release by mitochondria and stimulation of state 4 oxygen consumption. All of these effects are prevented by preincubating the mitochondria with cyclosporine A, a potent and specific inhibitor of the MPT. Therefore, VP-16 increases the sensitivity of isolated mitochondria to the Ca2+-dependent induction of the MPT. Together, these data provide a possible mechanistic explanation for the previously reported effects of VP-16 on apoptosis induction. |
publishDate |
2001 |
dc.date.none.fl_str_mv |
2001 |
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/10316/5799 http://hdl.handle.net/10316/5799 https://doi.org/10.1016/S0887-2333(01)00019-4 |
url |
http://hdl.handle.net/10316/5799 https://doi.org/10.1016/S0887-2333(01)00019-4 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Toxicology in Vitro. 15:4-5 (2001) 265-270 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
aplication/PDF |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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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) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799133750551904256 |