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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

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    Author
    Martelli, Alberto M.; Chiarini, Francesca; Evangelisti, Camilla; Cappellini, Alessandra; Buontempo, Francesca; Bressanin, Daniela; Fini, Milena; McCubrey, James A.
    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.
    URI
    http://hdl.handle.net/10342/5660
    Subject
     apoptosis; leukemia initiating cells; mRNA translation; PI3K/Akt/mTOR; targeted therapy 
    Date
    2012-04
    Citation:
    APA:
    Martelli, Alberto M., & Chiarini, Francesca, & Evangelisti, Camilla, & Cappellini, Alessandra, & Buontempo, Francesca, & Bressanin, Daniela, & Fini, Milena, & McCubrey, James A.. (April 2012). Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget, 3(4), 371- 394. Retrieved from http://hdl.handle.net/10342/5660

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    MLA:
    Martelli, Alberto M., and Chiarini, Francesca, and Evangelisti, Camilla, and Cappellini, Alessandra, and Buontempo, Francesca, and Bressanin, Daniela, and Fini, Milena, and McCubrey, James A.. "Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment". Oncotarget. 3:4. (371-394), April 2012. September 27, 2023. http://hdl.handle.net/10342/5660.
    Chicago:
    Martelli, Alberto M. and Chiarini, Francesca and Evangelisti, Camilla and Cappellini, Alessandra and Buontempo, Francesca and Bressanin, Daniela and Fini, Milena and McCubrey, James A., "Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment," Oncotarget 3, no. 4 (April 2012), http://hdl.handle.net/10342/5660 (accessed September 27, 2023).
    AMA:
    Martelli, Alberto M., Chiarini, Francesca, Evangelisti, Camilla, Cappellini, Alessandra, Buontempo, Francesca, Bressanin, Daniela, Fini, Milena, McCubrey, James A.. Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. April 2012; 3(4): 371-394. http://hdl.handle.net/10342/5660. Accessed September 27, 2023.
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