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

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    Author
    Lonetti, Annalisa; Cappellini, Alessandra; Spartà, Antonino Maria; Chiarini, Francesca; Buontempo, Francesca; Evangelisti, Camilla; Evangelisti, Cecilia; Orsini, Ester; McCubrey, James A.; Martelli, Alberto M.
    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.
    URI
    http://hdl.handle.net/10342/5569
    Subject
     PI3K isoforms; PTEN; T-ALL; targeted therapy; autophagy 
    Date
    2015-04
    Citation:
    APA:
    Lonetti, Annalisa, & Cappellini, Alessandra, & Spartà, Antonino Maria, & Chiarini, Francesca, & Buontempo, Francesca, & Evangelisti, Camilla, & Evangelisti, Cecilia, & Orsini, Ester, & McCubrey, James A., & Martelli, Alberto M.. (April 2015). PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors. Oncotarget, (6:12), p.10399-10414. Retrieved from http://hdl.handle.net/10342/5569

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    MLA:
    Lonetti, Annalisa, and Cappellini, Alessandra, and Spartà, Antonino Maria, and Chiarini, Francesca, and Buontempo, Francesca, and Evangelisti, Camilla, and Evangelisti, Cecilia, and Orsini, Ester, and McCubrey, James A., and Martelli, Alberto M.. "PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors". Oncotarget. 6:12. (10399-10414.), April 2015. August 17, 2022. http://hdl.handle.net/10342/5569.
    Chicago:
    Lonetti, Annalisa and Cappellini, Alessandra and Spartà, Antonino Maria and Chiarini, Francesca and Buontempo, Francesca and Evangelisti, Camilla and Evangelisti, Cecilia and Orsini, Ester and McCubrey, James A. and Martelli, Alberto M., "PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors," Oncotarget 6, no. 12 (April 2015), http://hdl.handle.net/10342/5569 (accessed August 17, 2022).
    AMA:
    Lonetti, Annalisa, Cappellini, Alessandra, Spartà, Antonino Maria, Chiarini, Francesca, Buontempo, Francesca, Evangelisti, Camilla, Evangelisti, Cecilia, Orsini, Ester, McCubrey, James A., Martelli, Alberto M.. PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors. Oncotarget. April 2015; 6(12) 10399-10414. http://hdl.handle.net/10342/5569. Accessed August 17, 2022.
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