Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Department of Immunology, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Int J Mol Sci. 2022 Jul 22;23(15):8084. doi: 10.3390/ijms23158084.
Cancer stem cells (CSCs) are in general characterized by higher resistance to cell death and cancer therapies than non-stem differentiated cancer cells. However, we and others have recently revealed using glioma stem cells (GSCs) as a model that, unexpectedly, CSCs have specific vulnerabilities that make them more sensitive to certain drugs compared with their differentiated counterparts. We aimed in this study to discover novel drugs targeting such Achilles' heels of GSCs as anti-GSC drug candidates to be used for the treatment of glioblastoma, the most therapy-resistant form of brain tumors. Here we report that domatinostat (4SC-202), a class I HDAC inhibitor, is one such candidate. At concentrations where it showed no or minimal growth inhibitory effect on differentiated GSCs and normal cells, domatinostat effectively inhibited the growth of GSCs mainly by inducing apoptosis. Furthermore, GSCs that survived domatinostat treatment lost their self-renewal capacity. These results suggested that domatinostat is a unique drug that selectively eliminates GSCs not only physically by inducing cell death but also functionally by inhibiting their self-renewal. Our findings also imply that class I HDACs and/or LSD1, another target of domatinostat, may possibly have a specific role in the maintenance of GSCs and therefore could be an attractive target in the development of anti-GSC therapies.
癌症干细胞（CSC）通常表现出比非干细胞分化癌细胞更高的抗细胞死亡和癌症治疗的能力。然而，我们和其他人最近用神经胶质瘤干细胞（GSC）作为模型揭示，出乎意料的是，CSC 具有特定的脆弱性，使它们对某些药物比其分化对应物更敏感。我们旨在本研究中发现针对 GSC 的此类阿喀琉斯之踵的新型药物作为用于治疗胶质母细胞瘤的抗 GSC 药物候选物，胶质母细胞瘤是最具治疗抵抗性的脑肿瘤形式。在这里，我们报告了一种这样的候选药物，即组蛋白脱乙酰酶（HDAC）抑制剂 1 类的 domatinostat（4SC-202）。在对分化的 GSC 和正常细胞显示出无或最小生长抑制作用的浓度下，domatinostat 通过诱导细胞凋亡有效地抑制 GSC 的生长。此外，在 domatinostat 处理后幸存的 GSC 失去了自我更新能力。这些结果表明，domatinostat 是一种独特的药物，不仅通过诱导细胞死亡从物理上选择性地消除 GSC，而且通过抑制其自我更新能力从功能上选择性地消除 GSC。我们的发现还表明，I 类 HDAC 和/或 domatinostat 的另一个靶标 LSD1，可能在 GSC 的维持中具有特定作用，因此可能是开发抗 GSC 治疗的有吸引力的靶标。
