天然化合物作为 NF2 缺陷型神经鞘瘤和脑膜瘤的潜在治疗方法：葫芦素 D 和去乙酰戈佐皂苷元。
Natural compounds as potential treatments of NF2-deficient schwannoma and meningioma: cucurbitacin D and goyazensolide.
机构信息
*Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital; †Departments of Otolaryngology, ‡Pediatrics, The Ohio State University College of Medicine; and §Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio, U.S.A.
出版信息
Otol Neurotol. 2013 Oct;34(8):1519-27. doi: 10.1097/MAO.0b013e3182956169.
HYPOTHESIS
Cucurbitacin D and goyazensolide, 2 plant-derived natural compounds, possess potent growth-inhibitory activity in schwannoma and meningioma cells.
BACKGROUND
Currently, no FDA-approved drugs are available for neurofibromatosis type 2 (NF2)-associated schwannomas and meningiomas. Selected natural compounds with antineoplastic activity, such as cucurbitacin D and goyazensolide, may be developed as potential treatments for these tumors.
METHODS
The Nf2-deficient mouse schwannoma Sch10545 and human benign meningioma Ben-Men-1 cells were treated with various concentrations of cucurbitacin D and goyazensolide. The effect on cell proliferation was determined using resazurin assays. Flow cytometry was used to assess the cell cycle profiles. Western blot analysis was performed to investigate the expression of various signaling molecules related to the cell cycle and the AKT pathway.
RESULTS
Cucurbitacin D inhibited proliferation of Sch10545 cells (IC50 ∼ 0.75 μM) and Ben-Men-1 cells (IC50 ∼0.2 μM). Goyazensolide also reduced cell proliferation of Sch10545 cells (IC50 ∼0.9 μM) and Ben-Men-1 cells (IC50 ∼1 μM). The G2/M population increased in both Sch10545 and Ben-Men-1 cells treated with cucurbitacin D or goyazensolide around the IC50. Cucurbitacin and goyazensolide substantially reduced the levels of cyclins E and A in treated Sch10545 and Ben-Men-1 cells. Cucurbitacin D also inhibited cyclin B, phospho-AKT and phospho-PRAS40 expression. In addition, goyazensolide reduced the levels of phospho-AKT and NFκB and increased the expression of pro-apoptotic Bim in Sch10545 and Ben-Men-1 cells.
CONCLUSION
Both cucurbitacin D and goyazensolide effectively inhibit proliferation of NF2-deficient schwannoma and meningioma cells, suggesting that these natural compounds should be further evaluated as potential treatments for NF2-related tumors.
假说
葫芦素 D 和 goyazensolide 这两种植物源性天然化合物对施万细胞瘤和脑膜瘤细胞具有很强的生长抑制活性。
背景
目前，尚无 FDA 批准的药物可用于治疗神经纤维瘤病 2 型（NF2）相关的施万细胞瘤和脑膜瘤。具有抗肿瘤活性的某些天然化合物，如葫芦素 D 和 goyazensolide，可能被开发为这些肿瘤的潜在治疗方法。
方法
用不同浓度的葫芦素 D 和 goyazensolide 处理 Nf2 缺陷型小鼠施万细胞瘤 Sch10545 和人良性脑膜瘤 Ben-Men-1 细胞。使用 Resazurin 测定法确定对细胞增殖的影响。使用流式细胞术评估细胞周期谱。通过 Western blot 分析研究与细胞周期和 AKT 通路相关的各种信号分子的表达。
结果
葫芦素 D 抑制 Sch10545 细胞（IC50∼0.75μM）和 Ben-Men-1 细胞（IC50∼0.2μM）的增殖。Goyazensolide 也降低了 Sch10545 细胞（IC50∼0.9μM）和 Ben-Men-1 细胞（IC50∼1μM）的细胞增殖。在 Sch10545 和 Ben-Men-1 细胞中，用葫芦素 D 或 goyazensolide 处理后，G2/M 期细胞群在 IC50 附近增加。葫芦素 D 和 goyazensolide 显著降低了处理后的 Sch10545 和 Ben-Men-1 细胞中环蛋白 E 和 A 的水平。葫芦素 D 还抑制了 cyclin B、phospho-AKT 和 phospho-PRAS40 的表达。此外，goyazensolide 降低了 phospho-AKT 和 NFκB 的水平，并增加了 Sch10545 和 Ben-Men-1 细胞中促凋亡 Bim 的表达。
结论
葫芦素 D 和 goyazensolide 均能有效抑制 NF2 缺陷型施万细胞瘤和脑膜瘤细胞的增殖，表明这些天然化合物应进一步评估作为 NF2 相关肿瘤的潜在治疗方法。
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