Oncotarget

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Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment

Alberto M. Martelli _, Francesca Chiarini, Camilla Evangelisti, Alessandra Cappellini, Francesca Buontempo, Daniela Bressanin, Milena Fini and James A. McCubrey

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Oncotarget. 2012; 3:371-394. https://doi.org/10.18632/oncotarget.477

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Abstract

Alberto M. Martelli1,2, Francesca Chiarini2, Camilla Evangelisti2, Alessandra Cappellini3, Francesca Buontempo4, Daniela Bressanin1, Milena Fini4 and James A. McCubrey5

1 Department of Human Anatomy, University of Bologna, Cellular Signalling Laboratory, Bologna, Italy

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

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

4 Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic Institute, Bologna, Italy

5 Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, USA

Received: April 8, 2012, Accepted: April 28, 2012, Published: May 4, 2012,

Keywords:apoptosis, leukemia initiating cells, mRNA translation, PI3K/Akt/mTOR, targeted therapy

Correspondence:

Alberto M. Martelli, email:

Abstract

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are two key components of the PI3K/Akt/mTOR signaling pathway. This signal transduction cascade regulates a wide range of physiological cell processes, that include differentiation, proliferation, apoptosis, autophagy, metabolism, motility, and exocytosis. However, constitutively active PI3K/Akt/mTOR signaling characterizes many types of tumors where it negatively influences response to therapeutic treatments. Hence, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors may improve cancer patient outcome. The PI3K/Akt/mTOR signaling cascade is overactive in acute leukemias, where it correlates with enhanced drug-resistance and poor prognosis. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds targeting the catalytic site of both kinases. In preclinical models, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against acute leukemia cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin. At variance with rapamycin, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenic protein translation. Therefore, they strongly reduced cell proliferation and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors may represent a promising option for future targeted therapies of acute leukemia patients.


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