Pastorino Olga, Gentile Maria Teresa, Mancini Alessandro, Del Gaudio Nunzio, Di Costanzo Antonella, Bajetto Adriana, Franco Paola, Altucci Lucia, Florio Tullio, Stoppelli Maria Patrizia, Colucci-D'Amato Luca
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy.
Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
Cancers (Basel). 2019 May 29;11(6):747. doi: 10.3390/cancers11060747.
Glioblastoma (GBM), a high-grade glioma (WHO grade IV), is the most aggressive form of brain cancer. Available treatment options for GBM involve a combination of surgery, radiation and chemotherapy but result in a poor survival outcome. GBM is a high-vascularized tumor and antiangiogenic drugs are widely used in GBM therapy as adjuvants to control abnormal vasculature. Vasculogenic mimicry occurs in GBM as an alternative vascularization mechanism, providing a means whereby GBM can escape anti-angiogenic therapies. Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of different histone deacetylase inhibitors (HDACis) to interfere with vasculogenic mimicry. We found that vorinostat (SAHA) and MC1568 inhibit tube formation by rat glioma C6 cells. Moreover, at sublethal doses for GBM cells, SAHA, trichostatin A (TSA), entinostat (MS275), and MC1568 significantly decrease tube formation by U87MG and by patient-derived human GBM cancer stem cells (CSCs). The reduced migration and invasion of HDACis-treated U87 cells, at least in part, may account for the inhibition of tube formation. In conclusion, our results indicate that HDACis are promising candidates for blocking vascular mimicry in GBM.
胶质母细胞瘤（GBM）是一种高级别胶质瘤（世界卫生组织IV级），是最具侵袭性的脑癌形式。GBM现有的治疗方案包括手术、放疗和化疗的联合，但生存结果不佳。GBM是一种高血管化肿瘤，抗血管生成药物作为辅助药物广泛用于GBM治疗，以控制异常血管。血管生成拟态在GBM中作为一种替代血管化机制出现，为GBM逃避抗血管生成治疗提供了一种途径。在这里，我们使用基质胶上的体外管形成试验，评估了不同组蛋白去乙酰化酶抑制剂（HDACi）干扰血管生成拟态的能力。我们发现伏立诺他（SAHA）和MC1568抑制大鼠胶质瘤C6细胞的管形成。此外，在对GBM细胞亚致死剂量下，SAHA、曲古抑菌素A（TSA）、恩替诺特（MS275）和MC1568显著减少U87MG和患者来源的人GBM癌干细胞（CSC）的管形成。HDACi处理的U87细胞迁移和侵袭减少，至少部分可以解释管形成的抑制。总之，我们的结果表明HDACi是阻断GBM中血管拟态的有前景的候选药物。
