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Src 酪氨酸激酶抑制剂与 X 射线对神经胶质瘤细胞系的联合作用。

SRC Tyrosine Kinase Inhibitor and X-rays Combined Effect on Glioblastoma Cell Lines.

机构信息

Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, 95123 Catania, Italy.

National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy.

出版信息

Int J Mol Sci. 2020 May 30;21(11):3917. doi: 10.3390/ijms21113917.

DOI:10.3390/ijms21113917
PMID:32486205
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7312922/
Abstract

Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at the origin of treatment failure. The aim of this work was to assess the therapeutic potential of a new targeted c-SRC inhibitor molecule, named Si306, in combination with X-rays on the human glioblastoma cell lines, comparing normoxia and hypoxia conditions. For this purpose, the dose modifying factor and oxygen enhancement ratio were calculated to evaluate the Si306 radiosensitizing effect. DNA damage and the repair capability were also studied from the kinetic of γ-H2AX immunodetection. Furthermore, motility processes being supposed to be triggered by hypoxia and irradiation, the role of c-SRC inhibition was also analyzed to evaluate the migration blockage by wound healing assay. Our results showed that inhibition of the c-SRC protein enhances the radiotherapy efficacy both in normoxic and hypoxic conditions. These data open new opportunities for GBM treatment combining radiotherapy with molecularly targeted drugs to overcome radioresistance.

摘要

胶质母细胞瘤（GBM）是最致命的肿瘤类型之一，尽管采用了包括手术、放疗和化疗在内的积极治疗方案，但仍存在高复发率。缺氧是 GBM 的一个特征，与放疗抵抗有关，并且已知是治疗失败的根源。本研究旨在评估新型靶向 c-SRC 抑制剂分子 Si306 与 X 射线联合应用于人类胶质母细胞瘤细胞系的治疗潜力，比较了常氧和缺氧条件下的效果。为此，计算了剂量修正因子和氧增强比，以评估 Si306 的放射增敏作用。还从 γ-H2AX 免疫检测的动力学研究了 DNA 损伤和修复能力。此外，由于假设缺氧和照射会触发迁移过程，还分析了 c-SRC 抑制的作用，以通过划痕愈合试验评估迁移阻断作用。研究结果表明，抑制 c-SRC 蛋白可增强常氧和缺氧条件下的放疗疗效。这些数据为联合放疗和分子靶向药物治疗 GBM 提供了新的机会，以克服放疗抵抗。

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