Παρακαλώ χρησιμοποιήστε αυτό το αναγνωριστικό για να παραπέμψετε ή να δημιουργήσετε σύνδεσμο προς αυτό το τεκμήριο:
https://hdl.handle.net/20.500.14279/1517
Τίτλος: | Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia | Συγγραφείς: | Roccaro, Aldo Maria Sacco, Antonio Pitsillides, Costas Husu, Emanuel Vesole, Steven Azab, Abdel Kareem Azab, Feda Melhem, Molly R. Ngo, Hai T. Quang, Phong Maiso, Patricia Runnels, Judith M. Liang, Meichih Wong, Kwok Kin Lin, Charles P. Ghobrial, Irène M. |
Major Field of Science: | Medical and Health Sciences | Field Category: | MEDICAL AND HEALTH SCIENCES | Λέξεις-κλειδιά: | Waldenstrom Macroglobulinemia;Immunoglobulin M;WM patients | Ημερομηνία Έκδοσης: | 21-Ιαν-2010 | Πηγή: | Blood, 2010, vol. 115, no. 3, pp. 559-569 | Volume: | 115 | Issue: | 3 | Start page: | 559 | End page: | 569 | Περιοδικό: | Blood | Περίληψη: | We have previously shown clinical activity of a mammalian target of rapamycin (mTOR) complex 1 inhibitor in Waldenstrom macroglobulinemia (WM). However, 50% of patients did not respond to therapy. We therefore examined mechanisms of activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR in WM, and mechanisms of overcoming resistance to therapy. We first demonstrated that primary WM cells show constitutive activation of the PI3K/Akt pathway, supported by decreased expression of phosphate and tensin homolog tumor suppressor gene (PTEN) at the gene and protein levels, together with constitutive activation of Akt and mTOR. We illustrated that dual targeting of the PI3K/mTOR pathway by the novel inhibitor NVP-BEZ235 showed higher cytotoxicity on WM cells compared with inhibition of the PI3K or mTOR pathways alone. In addition, NVPBEZ235 inhibited both rictor and raptor, thus abrogating the rictor-induced Akt phosphorylation. NVP-BEZ235 also induced significant cytotoxicity in WM cells in a caspase-dependent and -independent manner, through targeting the Forkhead box transcription factors. In addition, NVPBEZ235 targeted WM cells in the context of bone marrow microenvironment, leading to significant inhibition of migration, adhesion in vitro, and homing in vivo. These studies therefore show that dual targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM | URI: | https://hdl.handle.net/20.500.14279/1517 | ISSN: | 15280020 | DOI: | 10.1182/blood-2009-07-235747 | Rights: | © The American Society of Hematology | Type: | Article | Affiliation: | Massachusetts General Hospital | Affiliation: | Harvard University | Publication Type: | Peer Reviewed |
Εμφανίζεται στις συλλογές: | Άρθρα/Articles |
CORE Recommender
SCOPUSTM
Citations
84
checked on 14 Μαρ 2024
WEB OF SCIENCETM
Citations
74
Last Week
0
0
Last month
0
0
checked on 29 Οκτ 2023
Page view(s)
593
Last Week
0
0
Last month
25
25
checked on 14 Μαρ 2025
Google ScholarTM
Check
Altmetric
Όλα τα τεκμήρια του δικτυακού τόπου προστατεύονται από πνευματικά δικαιώματα