Gedunin is a natural tetranorterpenoid secondary metabolite found in plants of the Meliaceae family, which has been reported for its antiparasitic, antifungal and anticancer activities. Here, we describe the molecular mechanisms underlying the in vitro anti proliferative activity of gedunin (isolated from the mangrove plant Xylocarpus granatum) in human ovarian cancer cells. We observed that gedunin triggered severe ROS generation leading to DNA damage and cell cycle arrest in G2/M phase thus inhibiting cell proliferation. ROS upregulation also led to mitochondrial stress and membrane depolarization, which eventually resulted in mitochondria-mediated apoptosis following cytochrome C release, caspase 9, 3 activation, and PARP cleavage. Transmission electron microscopy of gedunin treated cells revealed sub-cellular features typical of apoptosis. Moreover, an upregulation in stress kinases like phospho-ERK 1/2, phospho-p38 and phospho-JNK was also observed in gedunin treated cells. Free radical scavenger N-Acetyl-L-Cysteine (NAC) reversed all these effects resulting in increased cell survival, abrogation of cell cycle arrest, rescue of mitochondrial membrane potential and suppression of apoptotic markers. Interestingly, gedunin is also an inhibitor of the evolutionarily conserved molecular chaperone Heat Shock Protein 90 (hsp90) responsible for maintaining cellular homeostasis. Targeting this chaperone could be an attractive strategy for developing cancer therapeutics since many oncogenic proteins are also client proteins of hsp90. Collectively, our findings provide insights into the molecular mechanism of action of gedunin, which may aid drug development efforts against ovarian cancer.

中文翻译：

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从红树林植物木香木（Xylocarpus granatum）分离得到的Gedunin通过G2 / M期阻滞和氧化应激介导的内在凋亡在卵巢癌细胞中发挥其抗增殖活性。

葛根素是在the科植物中发现的天然四降萜类次生代谢产物，据报道其具有抗寄生虫，抗真菌和抗癌活性。在这里，我们描述了在人体卵巢癌细胞中，葛根素（从红树林植物木薯颗粒中分离）的体外抗增殖活性的分子机制。我们观察到，葛根素引发严重的ROS生成，导致DNA损伤和G2 / M期细胞周期停滞，从而抑制细胞增殖。ROS的上调也导致线粒体应激和膜去极化，最终导致线粒体介导的细胞色素C释放，胱天蛋白酶9、3活化和PARP裂解后介导的凋亡。葛根素处理过的细胞的透射电子显微镜显示出典型的凋亡亚细胞特征。此外，在经过葛根素处理的细胞中还观察到应激激酶如磷酸化ERK 1/2，磷酸化p38和磷酸化JNK的上调。自由基清除剂N-乙酰基-L-半胱氨酸（NAC）逆转了所有这些作用，从而导致细胞存活率提高，细胞周期停滞废止，线粒体膜电位的挽救和凋亡标记的抑制。有趣的是，葛根素还是负责维持细胞稳态的进化上保守的分子伴侣热休克蛋白90（hsp90）的抑制剂。由于许多致癌蛋白也是hsp90的客户蛋白，因此靶向这种分子伴侣可能是开发癌症治疗方法的一种有吸引力的策略。总的来说，我们的发现提供了有关葛根素作用分子机制的见解，这可能有助于抗卵巢癌的药物开发。