Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease
Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in c...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/220318 |
| Acceso en línea: | http://hdl.handle.net/10261/220318 |
| Access Level: | acceso abierto |
| Palabra clave: | β-adrenergic receptor antagonist ICI-118,551 propranolol HIF ccRCC VHL Anticarcinogenic |
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Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau diseaseAlbiñana, VirginiaGallardo-Vara, EunateRojas-P, Isabel deRecio-Poveda, LucíaAguado, TaniaCanto-Cano, AnaAguirre, Daniel T.Serra, Marcelo M.González-Peramato, PilarMartínez-Piñeiro, LuisCuesta, Ángel M.Botella, Luisa Maríaβ-adrenergic receptor antagonistICI-118,551propranololHIFccRCCVHLAnticarcinogenicVon Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.This research was funded by Ministry of Economy and Competitivity, grant number SAF2017-83351-R. L.M-P. was supported by grants from Madrid Regional Government “IMMUNOTHERCAN” [B2017/BMD-3733-2]. A.M.C. was funded by the Spanish Alliance of VHL patients and V.A. was funded by CIBERER.Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/220318reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-83351-RSAF2017-83351-R/AEI/10.13039/501100011033B2017/BMD-3733-2/IMMUNOTHERCANhttps://doi.org/10.3390/jcm9092740Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2203182026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| title |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| spellingShingle |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease Albiñana, Virginia β-adrenergic receptor antagonist ICI-118,551 propranolol HIF ccRCC VHL Anticarcinogenic |
| title_short |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| title_full |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| title_fullStr |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| title_full_unstemmed |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| title_sort |
Targeting β2-adrenergic receptors shows therapeutical benefits in clear cell renal cell carcinoma from Von Hippel–Lindau disease |
| dc.creator.none.fl_str_mv |
Albiñana, Virginia Gallardo-Vara, Eunate Rojas-P, Isabel de Recio-Poveda, Lucía Aguado, Tania Canto-Cano, Ana Aguirre, Daniel T. Serra, Marcelo M. González-Peramato, Pilar Martínez-Piñeiro, Luis Cuesta, Ángel M. Botella, Luisa María |
| author |
Albiñana, Virginia |
| author_facet |
Albiñana, Virginia Gallardo-Vara, Eunate Rojas-P, Isabel de Recio-Poveda, Lucía Aguado, Tania Canto-Cano, Ana Aguirre, Daniel T. Serra, Marcelo M. González-Peramato, Pilar Martínez-Piñeiro, Luis Cuesta, Ángel M. Botella, Luisa María |
| author_role |
author |
| author2 |
Gallardo-Vara, Eunate Rojas-P, Isabel de Recio-Poveda, Lucía Aguado, Tania Canto-Cano, Ana Aguirre, Daniel T. Serra, Marcelo M. González-Peramato, Pilar Martínez-Piñeiro, Luis Cuesta, Ángel M. Botella, Luisa María |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
β-adrenergic receptor antagonist ICI-118,551 propranolol HIF ccRCC VHL Anticarcinogenic |
| topic |
β-adrenergic receptor antagonist ICI-118,551 propranolol HIF ccRCC VHL Anticarcinogenic |
| description |
Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020 2020 2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/220318 |
| url |
http://hdl.handle.net/10261/220318 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-83351-R SAF2017-83351-R/AEI/10.13039/501100011033 B2017/BMD-3733-2/IMMUNOTHERCAN https://doi.org/10.3390/jcm9092740 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Multidisciplinary Digital Publishing Institute |
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Multidisciplinary Digital Publishing Institute |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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