Wang Zhi, Zhu Yushuai, Luo Can, Zhang Fan, Zhao Jiannong, Fu Chuanyi
Department of Cerebrovascular Disease, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, PR China.
Department of Neurosurgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, PR China.
Heliyon. 2024 Dec 24;11(1):e41440. doi: 10.1016/j.heliyon.2024.e41440. eCollection 2025 Jan 15.
Gliomas are the most common primary tumors of the nervous system, which is generally treated using adjuvant chemotherapy following surgical resection. However, patient survival time is still short, and there is currently no successful treatment for highly malignant gliomas. Bullatine A (BLA) is a diterpenoid alkaloid of the genus Aconitum which antirheumatic and anti-inflammatory pharmacological properties. The effects of BLA on gliomas have not yet been elucidated. In this study, we investigated the effects of BLA on human brain malignant glioblastoma cells. Our results showed that BLA inhibited the proliferation of U87MG and U251 cells in a dose-dependent manner and decreased their survival rate. BLA dose-dependently induced apoptosis in U87MG cells, upregulated the expression of cleaved caspase-9, cleaved caspase-3 pro-apoptotic protein, and Bax protein, and downregulated the expression of Bcl-2 anti-apoptotic protein. Moreover, BLA dose-dependently induced U87MG and U251 cell cycle arrest in the G2/M phase, and downregulated the expression of p-ERK and Myc proteins. Further, BLA significantly inhibited the acetylation of histones H3K9 and H3K56, and upregulated the expression of the protein deacetylase SIRT6. Mechanistic studies revealed that the effect of BLA on inducing apoptosis and inhibiting the proliferation of glioma cells was blocked by SIRT6 knockout. In summary, our study indicated that BLA is a potential therapeutic agent for glioma that targets SIRT6 to inhibit glioma cell proliferation and induce apoptosis.
神经胶质瘤是神经系统最常见的原发性肿瘤，通常在手术切除后采用辅助化疗进行治疗。然而，患者的生存时间仍然较短，目前对于高度恶性神经胶质瘤尚无成功的治疗方法。布拉亭A（BLA）是乌头属的一种二萜生物碱，具有抗风湿和抗炎药理特性。BLA对神经胶质瘤的作用尚未阐明。在本研究中，我们调查了BLA对人脑恶性胶质母细胞瘤细胞的影响。我们的结果表明，BLA以剂量依赖性方式抑制U87MG和U251细胞的增殖，并降低其存活率。BLA剂量依赖性地诱导U87MG细胞凋亡，上调裂解的半胱天冬酶-9、裂解的半胱天冬酶-3促凋亡蛋白和Bax蛋白的表达，并下调Bcl-2抗凋亡蛋白的表达。此外，BLA剂量依赖性地诱导U87MG和U251细胞周期停滞于G2/M期，并下调p-ERK和Myc蛋白的表达。此外，BLA显著抑制组蛋白H3K9和H3K56的乙酰化，并上调蛋白脱乙酰酶SIRT6的表达。机制研究表明，SIRT6基因敲除可阻断BLA诱导神经胶质瘤细胞凋亡和抑制其增殖的作用。总之，我们的研究表明，BLA是一种潜在的神经胶质瘤治疗药物，其通过靶向SIRT6来抑制神经胶质瘤细胞增殖并诱导凋亡。
