SRC Family Kinase Inhibition Through a New Pyrazolo[3,4-d]Pyrimidine Derivative as a Feasible Approach for Glioblastoma Treatment
SRC Family Kinase Inhibition Through a New Pyrazolo[3,4-d]Pyrimidine Derivative as a Feasible Approach for Glioblastoma Treatment
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DOI：
10.1002/jcb.25042
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
Giordano, Antonio
中科院分区：
文献类型：
--
作者：
Ceccherini, Elisa;Indovina, Paola;Giordano, Antonio
胶质母细胞瘤（GB）是中枢神经系统最常见且最具侵袭性的原发性肿瘤。目前 GB 的护理标准包括手术切除，然后放疗联合替莫唑胺化疗。然而，尽管进行了这种强化治疗，预后仍然极差。因此，迫切需要更有效的治疗方法。最近的研究表明，SRC 家族激酶 (SFK) 可能代表 GB 治疗的有希望的分子靶点。在这里，我们用一种新的选择性吡唑并[3,4-d]嘧啶衍生物 SFK 抑制剂（称为 SI221）挑战了四种 GB 细胞系。通过 MTS 测定评估，该化合物对 GB 细胞具有显着的细胞毒性作用，但不会显着影响非肿瘤细胞（原代人皮肤成纤维细胞）。我们还观察到 SI221 在 GB 细胞中比众所周知的 SFK 抑制剂 PP2 更有效。值得注意的是，尽管 GB 细胞对细胞凋亡具有高度的内在抵抗力，但通过细胞荧光分析和 caspase-3 测定观察到，SI221 能够在所有 GB 细胞系中诱导这种细胞死亡过程。 SI221 还对 GB 细胞生长发挥长期抑制作用，并能够减少 GB 细胞迁移，分别如克隆形成试验和划痕试验所示。此外，通过体外药代动力学测定，SI221被证明具有较高的代谢稳定性和良好的穿过血脑屏障的潜力，这是治疗脑肿瘤的药物的基本要求。因此，尽管需要制定提高 SI221 溶解度的策略，但我们的结果表明这种选择性 SFK 抑制剂在 GB 治疗中的潜在应用。 J.细胞。生物化学。 116：856-863，2015。(C)2014 Wiley 期刊公司。
Glioblastoma (GB) is the most common and aggressive primary tumor of the central nervous system. The current standard of care for GB consists of surgical resection, followed by radiotherapy combined with temozolomide chemotherapy. However, despite this intensive treatment, the prognosis remains extremely poor. Therefore, more effective therapies are urgently required. Recent studies indicate that SRC family kinases (SFKs) could represent promising molecular targets for GB therapy. Here, we challenged four GB cell lines with a new selective pyrazolo[3,4-d]pyrimidine derivative SFK inhibitor, called SI221. This compound exerted a significant cytotoxic effect on GB cells, without significantly affecting non-tumor cells (primary human skin fibroblasts), as evaluated by MTS assay. We also observed that SI221 was more effective than the well-known SFK inhibitor PP2 in GB cells. Notably, despite the high intrinsic resistance to apoptosis of GB cells, SI221 was able to induce this cell death process in all the GB cell lines, as observed through cytofluorimetric analysis and caspase-3 assay. SI221 also exerted a long-term inhibition of GB cell growth and was able to reduce GB cell migration, as shown by clonogenic assay and scratch test, respectively. Moreover, through in vitro pharmacokinetic assays, SI221 proved to have a high metabolic stability and a good potential to cross the blood brain barrier, which is an essential requirement for a drug intended to treat brain tumors. Therefore, despite the need of developing strategies to improve SI221 solubility, our results suggest a potential application of this selective SFK inhibitor in GB therapy. J. Cell. Biochem. 116: 856-863, 2015. (C) 2014 Wiley Periodicals, Inc.