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