Oncotarget

Research Papers:

PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors

Annalisa Lonetti _, Alessandra Cappellini, Antonino Maria Spartà, Francesca Chiarini, Francesca Buontempo, Camilla Evangelisti, Cecilia Evangelisti, Ester Orsini, James A. McCubrey and Alberto Maria Martelli

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Oncotarget. 2015; 6:10399-10414. https://doi.org/10.18632/oncotarget.3295

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Abstract

Annalisa Lonetti1,*, Alessandra Cappellini2,*, Antonino Maria Spartà1, Francesca Chiarini3,4, Francesca Buontempo1, Camilla Evangelisti3,4, Cecilia Evangelisti1, Ester Orsini1, James A. McCubrey5, Alberto Maria Martelli1

1Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

2Department of Human, Social and Health Sciences, University of Cassino, Cassino, Italy

3Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy

4Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy

5Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

*These authors have contributed equally to this work

Correspondence to:

Alberto Maria Martelli, e-mail: [email protected]

Keywords: PI3K isoforms, PTEN, T-ALL, targeted therapy, autophagy

Received: January 14, 2015     Accepted: February 06, 2015     Published: March 16, 2015

ABSTRACT

Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition. Intriguingly, the dual p110γ/δ inhibitor IPI-145 was effective in Loucy cells, which are representative of early T-precursor (ETP)-ALL, a T-ALL subtype associated with a poor outcome. PTEN gene deletion did not confer a peculiar reliance of T-ALL cells on PI3K activity for their proliferation/survival, as PTEN was inactivated in PTEN non deleted cells, due to posttranslational mechanisms. PI3K pan-inhibition suppressed Akt activation and induced caspase-independent apoptosis. We further demonstrated that in some T-ALL cell lines, autophagy could exert a protective role against PI3K inhibition. Our findings strongly support clinical application of class I PI3K pan-inhibitors in T-ALL treatment, with the possible exception of ETP-ALL cases.


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