Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6080
Title: Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition
Authors: Cozzi, Martina
Giorgi, Francesca
Marcelli, Eleonora
Pentimalli, Francesca
Forte, Iris Maria
Schenone, Silvia
D’Urso, Vittorio
De Falco, Giulia
Botta, Maurizio 
Giordano, Antonio
Indovina, Paola
Keywords: SRC inhibitors; Burkitt lymphoma; CDK1; WEE1; AKT
Issue Date: 2012
Project: None 
Journal: CELL CYCLE
Abstract: 
Burkitt lymphoma (BL) is a highly aggressive B-cell neoplasm. Although intensive polychemotherapy regimens have proven very effective, they are associated with significant toxicities. Therefore, more rational therapies that selectively target the molecular abnormalities of BL are needed. Recent data suggest that the tyrosine kinase SRC could represent a therapeutic target for BL. We found that new pyrazolo[3,4-d]pyrimidine SRC inhibitors exerted a significant cytotoxic effect and induced apoptosis on two BL cell lines, as determined by MTS assays, cytofluorimetric analyses and caspase 3 assay. Notably, our SRC inhibitors proved to be more effective than the well-known SRC inhibitor PP 2 [4-amino-5- (4‑chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine] in BL cells. Moreover, our small molecules induced a G2/M arrest in BL cells through a possible new mechanism, whereby SRC inhibition hinders an AKT-WEE 1-cyclin-dependent kinase 1 (CDK1) axis, leading to inhibition of CDK1, the main trigger of entry into mitosis. By using a small-molecule inhibitor of WEE 1, a crucial CDK1 negative regulator, we were able to shift the balance toward apoptosis rather than growth arrest and enhance the efficacy of the SRC inhibitors, suggesting a possible use of these selective drugs in combination for a safe and efficient treatment of BL.
Description: 
41877
URI: http://hdl.handle.net/20.500.12779/6080
ISSN: 1538-4101
DOI: 10.4161/cc.11.5.19519
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