Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas
Author
Martín-Sánchez, Esperanza; Rodríguez-Pinilla, Socorro María; Sánchez-Beato, Margarita; Lombardía, Luís J.; Domínguez-González, Beatriz; Romero, Diana; Odqvist, Lina; García-Sanz, Pablo; Wozniak, Magdalena B.; Kurz, Guido; Blanco-Aparicio, Carmen; Mollejo, Manuela; Javier Alves, F.; Menárguez, Javier; González-Palacios, Fernando J.; Rodríguez Peraltó, José Luís; Ortíz-Romero, Pablo Luis; García, Juán Fernando; Bischoff, James R.; Piris, Miguel ÁngelEntity
UAM. Departamento de Anatomía PatológicaPublisher
Ferrata Storti FoundationDate
2013Citation
10.3324/haematol.2012.068510
Haematologica 98.1 (2013): 57-64
ISSN
0390-6078 (print); 1592-8721 (online)DOI
10.3324/haematol.2012.068510Funded by
This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and PI080856), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB is supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018)Editor's Version
http://dx.doi.org/10.3324/haematol.2012.068510Subjects
Peripheral T-cell lymphomas; hematologic malignancies; PTCL; phosphatidylinositol-3-kinases; MedicinaNote
Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgRights
© 2013 Ferrata Storti FoundationAbstract
Peripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy.
New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol-
3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol-
3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas.
Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering 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. The PIK3CD gene,
which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples,
and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of
phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor
GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We
identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase
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 phosphatidylinositol-3-kinase 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 tumor T cells ex vivo. These results
suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective
than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be
of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.
Files in this item
Google Scholar:Martín-Sánchez, Esperanza
-
Rodríguez-Pinilla, Socorro María
-
Sánchez-Beato, Margarita
-
Lombardía, Luís J.
-
Domínguez-González, Beatriz
-
Romero, Diana
-
Odqvist, Lina
-
García-Sanz, Pablo
-
Wozniak, Magdalena B.
-
Kurz, Guido
-
Blanco-Aparicio, Carmen
-
Mollejo, Manuela
-
Javier Alves, F.
-
Menárguez, Javier
-
González-Palacios, Fernando J.
-
Rodríguez Peraltó, José Luís
-
Ortíz-Romero, Pablo Luis
-
García, Juán Fernando
-
Bischoff, James R.
-
Piris, Miguel Ángel
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