Angelucci Adriano, Schenone Silvia, Gravina Giovanni Luca, Muzi Paola, Festuccia Claudio, Vicentini Carlo, Botta Maurizio, Bologna Mauro
Dip. Scienze Chirurgiche, University of L'Aquila, 67100 L'Aquila, Italy.
Eur J Cancer. 2006 Nov;42(16):2838-45. doi: 10.1016/j.ejca.2006.06.024. Epub 2006 Sep 14.
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.
在其生物学进展过程中，前列腺癌常常发展为依赖生长因子受体及其下游信号信使，包括c-Src。这方面的证据支持将c-Src作为预防肿瘤扩散的治疗靶点。两种新型吡唑并[3,4-d]嘧啶类c-Src抑制剂SI35和SI40被用于研究c-Src在控制前列腺癌细胞系PC3侵袭性表型中的作用。SI分子以时间和剂量依赖的方式降低PC3细胞的增殖，IC50约为50微摩尔。PC3细胞在表皮生长因子（EGF）存在时通过提高其迁移能力做出反应，而在加入浓度低于IC50的SI时，这种效应会显著降低。进一步观察表明，SI分子调节细胞形态及其在不同生理基质上的黏附能力。SI分子的作用似乎除了抑制c-Src外，还涉及下调桩蛋白和细胞外信号调节激酶（ERK）的活性形式。我们的数据表明吡唑并[3,4-d]嘧啶类c-Src抑制剂在控制高度侵袭性肿瘤表型方面具有广阔前景。
