Yuan Xuhui, Li Jiayu, Yu Bo, Cai Feng, Chen Binqi, Liu Jun, Peng Yuanxiang, Zeng Duo, Liao Qi, Liu Lang
Department of Orthopedics, The First Hospital of Nanchang, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Department of Orthopedics, Huaqiao Hospital, Jinan University, Guangzhou, China.
J Bone Oncol. 2025 Jun 20;53:100699. doi: 10.1016/j.jbo.2025.100699. eCollection 2025 Aug.
Osteosarcoma (OS) remains a highly aggressive malignancy with limited treatment options, necessitating the discovery of novel therapeutic agents. Demethylzeylasteral (DEM), a compound previously shown to exert anti-tumor properties in several malignancies, has not been sufficiently explored for its potential in OS treatment.
This study focused on the anti-tumor properties of DEM on OS cells as well as the potential mechanisms.
OS cell lines (MG63 and 143B) were exposed to varying concentrations of DEM, followed by assessment of diverse cell functions. RNA sequencing was implemented to identify the molecular pathways affected by DEM exposure. The mechanistic underpinnings of DEM's action were also studied via a series of assays. Additionally, the therapeutic potential was validated utilizing xenograft models.
DEM evidently repressed OS cell proliferation in a dose- and time-dependent fashion, arrested cells in G2/M phase, and facilitated apoptosis through the modulation of the BCL2/BAX ratio. Furthermore, DEM suppressed cell migration and invasion by reversing EMT-related protein expression. RNA sequencing revealed that DEM primarily affected autophagy-related pathways, particularly through the PI3K/AKT signaling. DEM treatment led to an elevation in ROS generation and enhanced autophagic activity, as demonstrated by elevated LC3B puncta formation and autophagy-related protein expression. , DEM effectively suppressed tumor growth while showing a favorable safety profile.
This study provides comprehensive evidence that DEM exerts potent anti-tumor properties in OS via the PI3K/AKT pathway, highlighting the significance of DEM as a therapeutic candidate for OS.
骨肉瘤（OS）仍然是一种侵袭性很强的恶性肿瘤，治疗选择有限，因此需要发现新的治疗药物。去甲基泽拉斯萜醇（DEM）是一种先前已证明在多种恶性肿瘤中具有抗肿瘤特性的化合物，但其在骨肉瘤治疗中的潜力尚未得到充分探索。
本研究聚焦于DEM对骨肉瘤细胞的抗肿瘤特性及其潜在机制。
将骨肉瘤细胞系（MG63和143B）暴露于不同浓度的DEM中，随后评估多种细胞功能。进行RNA测序以鉴定受DEM暴露影响的分子途径。还通过一系列实验研究了DEM作用的机制基础。此外，利用异种移植模型验证了其治疗潜力。
DEM明显以剂量和时间依赖性方式抑制骨肉瘤细胞增殖，使细胞停滞在G2/M期，并通过调节BCL2/BAX比值促进细胞凋亡。此外，DEM通过逆转与上皮-间质转化（EMT）相关的蛋白表达来抑制细胞迁移和侵袭。RNA测序显示，DEM主要影响自噬相关途径，特别是通过PI3K/AKT信号通路。DEM处理导致活性氧（ROS）生成增加和自噬活性增强，这通过LC3B斑点形成增加和自噬相关蛋白表达得以证明。此外，DEM有效抑制肿瘤生长，同时显示出良好的安全性。
本研究提供了全面的证据，表明DEM通过PI3K/AKT途径在骨肉瘤中发挥强大的抗肿瘤特性，突出了DEM作为骨肉瘤治疗候选药物的重要性。
