Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells

Background: The phosphatidylinositol-3-kinase/Akt pathway has been described to be critical in the survival of chronic lymphocytic leukemia cells. In this study we analyzed the effect of two selective chemical inhibitors of Akt (Akti-1/2 and A-443654) on the survival of chronic lymphocytic leukemia...

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Autores: Frías Sanchez, Mercè de, Iglesias i Serret, Daniel, Coll Mulet, Llorenç, Cosialls Castel, Ana Mª, Santidrián, Antonio F., González Gironés, Diana M., Banda, Esmeralda de la, Pons i Irazazábal, Gabriel, Gil i Santano, Joan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2009
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/126425
Acceso en línea:https://hdl.handle.net/2445/126425
Access Level:acceso abierto
Palabra clave:Leucèmia limfocítica crònica
Apoptosi
Chronic lymphocytic leukemia
Apoptosis
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repository_id_str
spelling Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cellsFrías Sanchez, Mercè deIglesias i Serret, DanielColl Mulet, LlorençCosialls Castel, Ana MªSantidrián, Antonio F.González Gironés, Diana M.Banda, Esmeralda de laPons i Irazazábal, GabrielGil i Santano, JoanLeucèmia limfocítica crònicaApoptosiChronic lymphocytic leukemiaApoptosisBackground: The phosphatidylinositol-3-kinase/Akt pathway has been described to be critical in the survival of chronic lymphocytic leukemia cells. In this study we analyzed the effect of two selective chemical inhibitors of Akt (Akti-1/2 and A-443654) on the survival of chronic lymphocytic leukemia cells. Design and Methods: Using cytometry we studied the cytotoxic effects of Akt inhibitors on peripheral B and T lymphocytes from patients with chronic lymphocytic leukemia and from healthy donors. We studied the changes induced by Akti-1/2 and A-443654 at the mRNA level by performing reverse transcriptase multiplex ligation-dependent probe amplification. We also studied the changes induced by both Akt inhibitors in some BCL-2 protein family members on chronic lymphocytic leukemia cells by western blotting. Moreover, we analyzed the cytotoxic effect of Akt inhibitors in patients' cells with deleted/mutated TP53. Results: Both inhibitors induced apoptosis in chronic lymphocytic leukemia cells in a dose-dependent manner. Moreover, B cells from patients with chronic lymphocytic leukemia were more sensitive to Akt inhibitors than T cells from leukemic patients, and B or T cells from healthy donors. Survival factors for chronic lymphocytic leukemia cells, such as interleukin-4 and stromal cell-derived factor-1 alpha, were not able to block the apoptosis induced by either Akt inhibitor. Akti-1/2 did not induce any change in the mRNA expression profile of genes involved in apoptosis, while A-443654 induced some changes, including an increase in NOXA and PUMA mRNA levels, suggesting the existence of additional targets for A-443654. Both inhibitors induced an increase in PUMA and NOXA protein levels, and a decrease in MCL-1 protein level. Moreover, Akti-1/2 and A-443654 induced apoptosis irrespective of TP53 status. Conclusions: These results demonstrate that Akt inhibitors induce apoptosis of chronic lymphocytic leukemia cells and might be a new therapeutic option for the treatment of chronic lymphocytic leukemia.Ferrata Storti Foundation2018201820092018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion10 p.application/pdfhttps://hdl.handle.net/2445/126425Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3324/haematol.2008.004028Haematologica, 2009, vol. 94, num. 12, p. 1698-1707https://doi.org/10.3324/haematol.2008.004028cc-by-nc (c) Ferrata Storti Foundation, 2009http://creativecommons.org/licenses/by-nc/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1264252026-05-29T05:05:01Z
dc.title.none.fl_str_mv Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
title Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
spellingShingle Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
Frías Sanchez, Mercè de
Leucèmia limfocítica crònica
Apoptosi
Chronic lymphocytic leukemia
Apoptosis
title_short Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
title_full Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
title_fullStr Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
title_full_unstemmed Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
title_sort Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells
dc.creator.none.fl_str_mv Frías Sanchez, Mercè de
Iglesias i Serret, Daniel
Coll Mulet, Llorenç
Cosialls Castel, Ana Mª
Santidrián, Antonio F.
González Gironés, Diana M.
Banda, Esmeralda de la
Pons i Irazazábal, Gabriel
Gil i Santano, Joan
author Frías Sanchez, Mercè de
author_facet Frías Sanchez, Mercè de
Iglesias i Serret, Daniel
Coll Mulet, Llorenç
Cosialls Castel, Ana Mª
Santidrián, Antonio F.
González Gironés, Diana M.
Banda, Esmeralda de la
Pons i Irazazábal, Gabriel
Gil i Santano, Joan
author_role author
author2 Iglesias i Serret, Daniel
Coll Mulet, Llorenç
Cosialls Castel, Ana Mª
Santidrián, Antonio F.
González Gironés, Diana M.
Banda, Esmeralda de la
Pons i Irazazábal, Gabriel
Gil i Santano, Joan
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia limfocítica crònica
Apoptosi
Chronic lymphocytic leukemia
Apoptosis
topic Leucèmia limfocítica crònica
Apoptosi
Chronic lymphocytic leukemia
Apoptosis
description Background: The phosphatidylinositol-3-kinase/Akt pathway has been described to be critical in the survival of chronic lymphocytic leukemia cells. In this study we analyzed the effect of two selective chemical inhibitors of Akt (Akti-1/2 and A-443654) on the survival of chronic lymphocytic leukemia cells. Design and Methods: Using cytometry we studied the cytotoxic effects of Akt inhibitors on peripheral B and T lymphocytes from patients with chronic lymphocytic leukemia and from healthy donors. We studied the changes induced by Akti-1/2 and A-443654 at the mRNA level by performing reverse transcriptase multiplex ligation-dependent probe amplification. We also studied the changes induced by both Akt inhibitors in some BCL-2 protein family members on chronic lymphocytic leukemia cells by western blotting. Moreover, we analyzed the cytotoxic effect of Akt inhibitors in patients' cells with deleted/mutated TP53. Results: Both inhibitors induced apoptosis in chronic lymphocytic leukemia cells in a dose-dependent manner. Moreover, B cells from patients with chronic lymphocytic leukemia were more sensitive to Akt inhibitors than T cells from leukemic patients, and B or T cells from healthy donors. Survival factors for chronic lymphocytic leukemia cells, such as interleukin-4 and stromal cell-derived factor-1 alpha, were not able to block the apoptosis induced by either Akt inhibitor. Akti-1/2 did not induce any change in the mRNA expression profile of genes involved in apoptosis, while A-443654 induced some changes, including an increase in NOXA and PUMA mRNA levels, suggesting the existence of additional targets for A-443654. Both inhibitors induced an increase in PUMA and NOXA protein levels, and a decrease in MCL-1 protein level. Moreover, Akti-1/2 and A-443654 induced apoptosis irrespective of TP53 status. Conclusions: These results demonstrate that Akt inhibitors induce apoptosis of chronic lymphocytic leukemia cells and might be a new therapeutic option for the treatment of chronic lymphocytic leukemia.
publishDate 2009
dc.date.none.fl_str_mv 2009
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/126425
url https://hdl.handle.net/2445/126425
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3324/haematol.2008.004028
Haematologica, 2009, vol. 94, num. 12, p. 1698-1707
https://doi.org/10.3324/haematol.2008.004028
dc.rights.none.fl_str_mv cc-by-nc (c) Ferrata Storti Foundation, 2009
http://creativecommons.org/licenses/by-nc/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc (c) Ferrata Storti Foundation, 2009
http://creativecommons.org/licenses/by-nc/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv Ferrata Storti Foundation
publisher.none.fl_str_mv Ferrata Storti Foundation
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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