Lv Cuiting, Qin Wenxing, Zhu Tonghan, Wei Shanjian, Hong Kui, Zhu Weiming, Chen Ruohua, Huang Caiguo
Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
Teaching Management Department, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
Mar Drugs. 2015 Jan 16;13(1):431-43. doi: 10.3390/md13010431.
Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.
蛇孢菌素O是蛇孢菌素家族的一员，已被证明是一种有潜力的治疗人类乳腺癌的抗癌药物候选物。然而，蛇孢菌素O的抗肿瘤作用及其机制仍不清楚。在本研究中，我们进一步证实了蛇孢菌素O可诱导人乳腺癌MCF-7细胞发生G1期阻滞，并发现蛇孢菌素O降低了AKT和GSK3β的磷酸化水平，并诱导细胞周期蛋白D1下调。反向对接（INVDOCK）分析表明，蛇孢菌素O可与GSK3β结合，敲低GSK3β可消除细胞周期蛋白D1的降解和G1期阻滞。用磷酸酶抑制剂钠或钒酸钠预处理可阻止AKT和GSK3β的去磷酸化，并阻断蛇孢菌素O诱导的G1期阻滞。这些数据表明，蛇孢菌素O可能通过与AKT/GSK3β/细胞周期蛋白D1信号通路相互作用，诱导MCF-7细胞发生G1期阻滞。在体内，蛇孢菌素O可抑制小鼠异种移植模型中的肿瘤生长，且毒性较小。总体而言，这些发现为蛇孢菌素O的治疗应用提供了理论依据。
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