Cargando…

Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo

Targeted drugs have significantly improved the therapeutic options for advanced renal cell carcinoma (RCC). However, resistance often develops, negating the benefit of these agents. In the present study, the molecular mechanisms of acquired resistance towards the histone deacetylase (HDAC) inhibitor...

Descripción completa

Detalles Bibliográficos
Autores principales: Juengel, Eva, Makarević, Jasmina, Tsaur, Igor, Bartsch, Georg, Nelson, Karen, Haferkamp, Axel, Blaheta, Roman A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553088/
https://www.ncbi.nlm.nih.gov/pubmed/23372654
http://dx.doi.org/10.1371/journal.pone.0053100
_version_ 1782256781608615936
author Juengel, Eva
Makarević, Jasmina
Tsaur, Igor
Bartsch, Georg
Nelson, Karen
Haferkamp, Axel
Blaheta, Roman A.
author_facet Juengel, Eva
Makarević, Jasmina
Tsaur, Igor
Bartsch, Georg
Nelson, Karen
Haferkamp, Axel
Blaheta, Roman A.
author_sort Juengel, Eva
collection PubMed
description Targeted drugs have significantly improved the therapeutic options for advanced renal cell carcinoma (RCC). However, resistance often develops, negating the benefit of these agents. In the present study, the molecular mechanisms of acquired resistance towards the histone deacetylase (HDAC) inhibitor valproic acid (VPA) in a RCC in vivo model were investigated. NMRI:nu/nu mice were transplanted with Caki-1 RCC cells and then treated with VPA (200 mg/kg/day). Controls remained untreated. Based on tumor growth dynamics, the mice were divided into “responders” and “non-responders” to VPA. Histone H3 and H4 acetylation and expression of cell signaling and cell cycle regulating proteins in the RCC mouse tumors were evaluated by Western blotting. Tumor growth of VPA responders was significantly diminished, whereas that of VPA non-responders even exceeded control values. Cdk1, 2 and 4 proteins were strongly enhanced in the non-responders. Importantly, Akt expression and activity were massively up-regulated in the tumors of the VPA non-responders. Chronic application (12 weeks) of VPA to Caki-1 cells in vitro evoked a distinct elevation of Akt activity and cancer cells no longer responded with cell growth reduction, compared to the short 2 week treatment. We assume that chronic use of an HDAC-inhibitor is associated with (re)-activation of Akt, which may be involved in resistance development. Consequently, combined blockade of both HDAC and Akt may delay or prevent drug resistance in RCC.
format Online
Article
Text
id pubmed-3553088
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-35530882013-01-31 Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo Juengel, Eva Makarević, Jasmina Tsaur, Igor Bartsch, Georg Nelson, Karen Haferkamp, Axel Blaheta, Roman A. PLoS One Research Article Targeted drugs have significantly improved the therapeutic options for advanced renal cell carcinoma (RCC). However, resistance often develops, negating the benefit of these agents. In the present study, the molecular mechanisms of acquired resistance towards the histone deacetylase (HDAC) inhibitor valproic acid (VPA) in a RCC in vivo model were investigated. NMRI:nu/nu mice were transplanted with Caki-1 RCC cells and then treated with VPA (200 mg/kg/day). Controls remained untreated. Based on tumor growth dynamics, the mice were divided into “responders” and “non-responders” to VPA. Histone H3 and H4 acetylation and expression of cell signaling and cell cycle regulating proteins in the RCC mouse tumors were evaluated by Western blotting. Tumor growth of VPA responders was significantly diminished, whereas that of VPA non-responders even exceeded control values. Cdk1, 2 and 4 proteins were strongly enhanced in the non-responders. Importantly, Akt expression and activity were massively up-regulated in the tumors of the VPA non-responders. Chronic application (12 weeks) of VPA to Caki-1 cells in vitro evoked a distinct elevation of Akt activity and cancer cells no longer responded with cell growth reduction, compared to the short 2 week treatment. We assume that chronic use of an HDAC-inhibitor is associated with (re)-activation of Akt, which may be involved in resistance development. Consequently, combined blockade of both HDAC and Akt may delay or prevent drug resistance in RCC. Public Library of Science 2013-01-23 /pmc/articles/PMC3553088/ /pubmed/23372654 http://dx.doi.org/10.1371/journal.pone.0053100 Text en © 2013 Juengel et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Juengel, Eva
Makarević, Jasmina
Tsaur, Igor
Bartsch, Georg
Nelson, Karen
Haferkamp, Axel
Blaheta, Roman A.
Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo
title Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo
title_full Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo
title_fullStr Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo
title_full_unstemmed Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo
title_short Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo
title_sort resistance after chronic application of the hdac-inhibitor valproic acid is associated with elevated akt activation in renal cell carcinoma in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553088/
https://www.ncbi.nlm.nih.gov/pubmed/23372654
http://dx.doi.org/10.1371/journal.pone.0053100
work_keys_str_mv AT juengeleva resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo
AT makarevicjasmina resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo
AT tsaurigor resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo
AT bartschgeorg resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo
AT nelsonkaren resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo
AT haferkampaxel resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo
AT blahetaromana resistanceafterchronicapplicationofthehdacinhibitorvalproicacidisassociatedwithelevatedaktactivationinrenalcellcarcinomainvivo