title: Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition.
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 PP2 [4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine] in BL cells. Moreover, our small molecules induced a G 2/M arrest in BL cells through a possible new mechanism, whereby SRC inhibition hinders an AKT-WEE1-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 WEE1, 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.
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, Siena, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Cozzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Giorgi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Marcelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
authors.forename: Iris Maria
authors.initials: IM
authors.lastname: Forte
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Vittorio
authors.initials: V
authors.lastname: D'Urso
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Paola
authors.initials: P
authors.lastname: Indovina
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C412373:AG 1879; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D019061:src-Family Kinases; D016203:CDC2 Protein Kinase