Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment
dc.contributor.author | Martelli, Alberto M. | |
dc.contributor.author | Chiarini, Francesca | |
dc.contributor.author | Evangelisti, Camilla | |
dc.contributor.author | Cappellini, Alessandra | |
dc.contributor.author | Buontempo, Francesca | |
dc.contributor.author | Bressanin, Daniela | |
dc.contributor.author | Fini, Milena | |
dc.contributor.author | McCubrey, James A. | |
dc.date.accessioned | 2016-06-16T17:41:11Z | |
dc.date.available | 2016-06-16T17:41:11Z | |
dc.date.issued | 2012-04 | |
dc.description.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. | en_US |
dc.identifier.citation | Oncotarget; 3:4 p. 371-394 | en_US |
dc.identifier.issn | 1949-2553 | |
dc.identifier.pmid | pmc3380573 | en_US |
dc.identifier.uri | http://hdl.handle.net/10342/5660 | |
dc.relation.uri | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380573/ | en_US |
dc.subject | apoptosis | en_US |
dc.subject | leukemia initiating cells | en_US |
dc.subject | mRNA translation | en_US |
dc.subject | PI3K/Akt/mTOR | en_US |
dc.subject | targeted therapy | en_US |
dc.title | Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment | en_US |
dc.type | Article | en_US |
ecu.journal.issue | 4 | en_US |
ecu.journal.name | Oncotarget | en_US |
ecu.journal.pages | 371-394 | en_US |
ecu.journal.volume | 3 | en_US |
Files
Original bundle
1 - 1 of 1
Loading...
- Name:
- oncotarget-03-371.PMC3380573.pdf
- Size:
- 1.43 MB
- Format:
- Adobe Portable Document Format