Mitochondrial permeability transition induced by the anticancer drug etoposide

Detalhes bibliográficos
Autor(a) principal: Custódio, J. B. A.
Data de Publicação: 2001
Outros Autores: Cardoso, C. M. P., Madeira, V. M. C., Almeida, L. M.
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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spelling 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
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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
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eu_rights_str_mv openAccess
dc.format.none.fl_str_mv aplication/PDF
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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