Zhao Yue, Liang Haiyue, Cui Xinmu
Department of Traditional Chinese Medicine, Yantaishan Hospital, Yantai, 264000, Shandong, China.
Department of Drug Business Management, Yantai Center for Food and Drug Control, Yantai, 264000, Shandong, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 21. doi: 10.1007/s00210-024-03738-9.
Ovarian cancer is characterized by a high rate of recurrence and a poor prognosis. Ferroptosis, a programmed cell death that is dependent on iron and lipid peroxidation, has emerged as a novel therapeutic target in recent years. This study investigated the effects of Obacunone, a naturally occurring compound present in citrus fruits, on the induction of ferroptosis in ovarian cancer via the Akt/p53 signaling pathway. SKOV3 and OVCAR3 ovarian cancer cell lines were utilized in vitro, while a BALB/c nude mouse model was employed for in vivo experiments. Cell proliferation was assessed utilizing the CCK-8 assay and EDU incorporation. The western blot technique was employed to assess the expression levels of proteins associated with the Akt/p53 signaling pathway. The ferroptosis inhibitor Fer-1 and the Akt activator SC79 were utilized to investigate the potential mechanism of action of Obacunone. Obacunone significantly inhibited the proliferation of ovarian cancer cells and induced ferroptosis, as evidenced by increased intracellular iron content, elevated lipid peroxidation levels, and abnormal mitochondrial morphology. Obacunone also decreased GSH levels, inhibited GPX4 expression and up-regulated ACSL4, as well as reduced Akt phosphorylation and enhanced p53 expression. In vivo experiments showed that Obacunone effectively inhibited tumor growth. Obacunone exhibits potential therapeutic significance through the modulation of the Akt/p53 signaling pathway, which may induce ferroptosis and inhibit the proliferation of ovarian cancer cells.
卵巢癌的特点是复发率高且预后差。铁死亡是一种依赖铁和脂质过氧化的程序性细胞死亡，近年来已成为一种新的治疗靶点。本研究调查了柑橘类水果中天然存在的化合物奥巴库酮通过Akt/p53信号通路诱导卵巢癌细胞铁死亡的作用。体外实验采用SKOV3和OVCAR3卵巢癌细胞系，体内实验采用BALB/c裸鼠模型。利用CCK-8法和EDU掺入法评估细胞增殖。采用蛋白质印迹技术评估与Akt/p53信号通路相关的蛋白质表达水平。利用铁死亡抑制剂Fer-1和Akt激活剂SC79研究奥巴库酮的潜在作用机制。奥巴库酮显著抑制卵巢癌细胞增殖并诱导铁死亡，表现为细胞内铁含量增加、脂质过氧化水平升高和线粒体形态异常。奥巴库酮还降低了谷胱甘肽（GSH）水平，抑制了谷胱甘肽过氧化物酶4（GPX4）表达并上调了长链脂酰辅酶A合成酶4（ACSL4），同时降低了Akt磷酸化水平并增强了p53表达。体内实验表明奥巴库酮有效抑制肿瘤生长。奥巴库酮通过调节Akt/p53信号通路展现出潜在的治疗意义，该通路可能诱导铁死亡并抑制卵巢癌细胞的增殖。
