Fraxetin is a coumarin scaffold compound extracted from Fraxinus rhynchophylla. It has antioxidant, anti-inflammatory, hepatoprotective, and antifibrotic effects. Furthermore, fraxetin has anticancer effects in breast and lung cancer. We aimed to evaluate whether fraxetin has anticancer activity in hepatocellular carcinoma (HCC) cells and its underlying mechanism. We demonstrated the anticancer effects of fraxetin in the HCC cell lines Huh7 and Hep3B. We confirmed that fraxetin inhibited cell proliferation (42% ± 10% Huh7; 52% ± 7% Hep3B) by arresting the cell cycle and inducing apoptosis in both cell lines. Moreover, fraxetin increased reactive oxygen species production (221% ± 55% Huh7; 460% ± 73% Hep3B), depolarized the mitochondrial membranes (ΔΨm) (345% ± 160% Huh7; 462% ± 140% Hep3B), and disrupted calcium homeostasis in both HCC cell lines. Chelating calcium ions with BAPTA-AM restored proliferation in fraxetin-treated Huh7 cells but not in Hep3B cells. Fraxetin did not affect the phosphorylation of extracellular-signal-regulated kinase 1/2, whereas it decreased JNK and phosphoinositide 3-kinase signaling. Furthermore, fraxetin and mitogen-activated protein kinase pharmacological inhibitors had synergistic antiproliferative effects on HCC cells. Although our study was limited to in vitro data that require validation, we suggest that fraxetin is a potential therapeutic agent against HCC progression.

中文翻译：

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Fraxetin抑制细胞增殖并通过人类肝细胞癌细胞系Huh7和Hep3B的线粒体功能障碍诱导细胞凋亡。

Fraxetin是从提取的香豆素骨架化合物白蜡曲柳 。它具有抗氧化，抗炎，保肝和抗纤维化的作用。此外，法拉西汀在乳腺癌和肺癌中具有抗癌作用。我们旨在评估法拉西汀是否在肝细胞癌（HCC）细胞中具有抗癌活性及其潜在机制。我们证明了法拉西汀在HCC细胞系Huh7和Hep3B中的抗癌作用。我们证实，法拉西汀通过阻滞细胞周期并诱导两种细胞系的凋亡来抑制细胞增殖（42％±10％Huh7； 52％±7％Hep3B）。此外，法拉西汀增加了活性氧的产生（221％±55％Huh7; 460％±73％Hep3B），使线粒体膜（ΔΨm）去极化（345％±160％Huh7; 462％±140％Hep3B），并破坏了钙两种HCC细胞系均具有稳态。用BAPTA-AM螯合钙离子可恢复经曲黄素处理的Huh7细胞的增殖，但不能恢复Hep3B细胞的增殖。Fraxetin不会影响细胞外信号调节激酶1/2的磷酸化，而会降低JNK和磷酸肌醇3激酶的信号传导。此外，弗拉西汀和丝裂原活化的蛋白激酶药理抑制剂对HCC细胞具有协同的抗增殖作用。尽管我们的研究仅限于需要验证的体外数据，但我们建议弗拉西汀是对抗HCC进展的潜在治疗剂。fraxetin和丝裂原激活的蛋白激酶药理抑制剂对HCC细胞具有协同的抗增殖作用。尽管我们的研究仅限于需要验证的体外数据，但我们建议，弗拉西汀是对抗HCC进展的潜在治疗剂。fraxetin和丝裂原激活的蛋白激酶药理抑制剂对HCC细胞具有协同的抗增殖作用。尽管我们的研究仅限于需要验证的体外数据，但我们建议，弗拉西汀是对抗HCC进展的潜在治疗剂。