Document Detail


Simultaneous pan-PI3K and MEK inhibition as a potential therapeutic strategy in peripheral T cell lymphomas.
MedLine Citation:
PMID:  22801959     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background. Peripheral T cell lymphomas are very aggressive hematological malignancies for which there is no targeted therapy. Therefore, new rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol-3-kinase (PI3K) is one of the most important pathways in cell survival and proliferation. We hypothesized that PI3K inhibitors could be rationally selected drugs for treating peripheral T cell lymphomas. Design and Methods. Several PI3K isoforms were inhibited genetically (using small interference RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot.Results. The PIK3CD gene, which encodes PI3Kδ, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological PI3Kδ inhibition affected cell survival. In contrast, the pan-PI3K inhibitor GDC-0941 arrested all T cell lymphoma cell lines at G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3β and phospho-p70S6K as potential biomarkers of PI3K inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T cell lymphoma cell lines, suggesting the presence of a combination of PI3K and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T cell lymphoma cell lines, and reducing cell viability in primary tumoral T cells ex vivo.Conclusions. These results suggest that the combined treatment of pan-PI3K + MEK inhibitors could be more effective than single PI3K inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T cell lymphomas.
Authors:
Esperanza Martin-Sanchez; Socorro Maria Rodriguez-Pinilla; Margarita Sanchez-Beato; Luis Lombardia; Beatriz Dominguez-Gonzalez; Diana Romero; Lina Odqvist; Pablo Garcia-Sanz; Magdalena B Wozniak; Guido Kurz; Carmen Blanco; Manuela Mollejo; Francisco Javier Alves; Javier Menarguez; Fernando Gonzalez-Palacios; Jose' Luis Rodriguez-Peralto; Pablo L Ortiz-Romero; Juan Fernando Garcia; James R Bischoff; Miguel A Piris
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-16
Journal Detail:
Title:  Haematologica     Volume:  -     ISSN:  1592-8721     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Spain;
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