title: Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells.
abstract: During its biological progression, prostate cancer frequently develops dependence on growth factor receptors and their downstream signalling messengers, including c-Src. Evidence for this supports the choice of c-Src as a therapeutic target in the prevention of tumour spreading. Two new pyrazolo[3,4-d]pyrimidines c-Src inhibitors, SI35 and SI40, were used to investigate the role of c-Src in the control of the aggressive phenotype of prostate carcinoma cell line, PC3. SI molecules reduced the proliferation of PC3 cells in a time- and dose-dependent manner, with an IC50 of approximately 50 microM. PC3 cells responded to the presence of epidermal growth factor (EGF) by increasing their migratory ability, and this effect was strongly reduced by the addition of SI at concentrations less than IC50. Further observations demonstrated that SI molecules modulated cell morphology and their adhesive capacity on different physiological substrates. The action of SI molecules appeared to involve, in parallel with c-Src inhibition, the down-modulation of the active forms of paxillin and extracellular signal-regulated kinase (ERK). Our data suggest a promising role for pyrazolo[3,4-d]pyrimidines c-Src inhibitors in the control of a highly invasive tumour phenotype.
authors.affiliation: Dip. Scienze Chirurgiche, University of L'Aquila, 67100 L'Aquila, Italy. adriano.angelucci@gmail.com
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Paola
authors.initials: P
authors.lastname: Muzi
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.forename: Carlo
authors.initials: C
authors.lastname: Vicentini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D016391:Genes, src; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D011720:Pyrazoles / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D004815:Epidermal Growth Factor