Nakagawa-Saito Yurika, Ito Yasufumi, Nakamura Kazuki, Mitobe Yuta, Togashi Keita, Suzuki Shuhei, Takenouchi Senri, Sugai Asuka, Sonoda Yukihiko, Kitanaka Chifumi, Okada Masashi
Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Department of Obstetrics and Gynecology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Int J Mol Sci. 2025 Aug 13;26(16):7803. doi: 10.3390/ijms26167803.
Domatinostat is an inhibitor of class I histone deacetylases, whose safety and efficacy as a cancer therapeutic has been demonstrated in a recent phase II study in patients with esophagogastric adenocarcinoma. We previously showed that domatinostat exhibited preferential cytotoxic activity against glioma stem cells (GSCs) compared to their differentiated counterparts. However, the underlying mechanism behind the preferential cytotoxicity is yet to be elucidated. In this study, we examined the effects of domatinostat treatment, as well as those of the knockdown of p53 or BAX or of the overexpression of BAX, on the expression of p53, BAX, and cleaved caspase substrates and on cell death in GSCs and their isogenic, differentiated counterparts. The results obtained indicated that domatinostat induced caspase-dependent apoptotic cell death preferentially in GSCs, which was accompanied by increased BAX expression in GSCs, but not in their differentiated counterparts. The increased BAX expression was required for domatinostat-induced GSC death, whereas BAX overexpression was sufficient to induce cell death in both GSCs and their differentiated counterparts. Notably, the expression of BAX after domatinostat treatment showed an early, p53-independent increase followed by a late, p53-dependent one. Together, the results suggest that the unique ability of domatinostat to activate the p53-dependent and -independent programs of BAX expression selectively in GSCs could account for its preferential cytotoxicity against GSCs. Our findings may also help guide the selection of patients with glioblastoma, and possibly those with other types of cancer, who are most likely to benefit from domatinostat treatment and optimize the treatment strategy for such patients.
多马替尼是一种I类组蛋白去乙酰化酶抑制剂，其作为癌症治疗药物的安全性和有效性已在最近一项针对食管胃腺癌患者的II期研究中得到证实。我们之前表明，与分化的神经胶质瘤干细胞（GSCs）相比，多马替尼对GSCs表现出优先的细胞毒性活性。然而，这种优先细胞毒性背后的潜在机制尚待阐明。在本研究中，我们研究了多马替尼处理以及p53或BAX基因敲低或BAX过表达对GSCs及其同基因分化对应细胞中p53、BAX和裂解的半胱天冬酶底物表达以及细胞死亡的影响。所得结果表明，多马替尼优先在GSCs中诱导依赖半胱天冬酶的凋亡性细胞死亡，这伴随着GSCs中BAX表达的增加，但在其分化对应细胞中未增加。多马替尼诱导的GSC死亡需要BAX表达增加，而BAX过表达足以在GSCs及其分化对应细胞中诱导细胞死亡。值得注意的是，多马替尼处理后BAX的表达显示出早期的、不依赖p53的增加，随后是晚期的、依赖p53的增加。总之，这些结果表明，多马替尼在GSCs中选择性激活依赖p53和不依赖p53的BAX表达程序的独特能力可能解释了其对GSCs的优先细胞毒性。我们的发现也可能有助于指导胶质母细胞瘤患者以及可能患有其他类型癌症的患者的选择，这些患者最有可能从多马替尼治疗中受益，并优化此类患者的治疗策略。
