Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.

Cepharanthine (CEP) 是一种从千金藤中提取的生物活性化合物，对多种恶性肿瘤具有细胞毒性。然而，胃癌的潜在机制尚不清楚。本研究中CEP抑制胃癌AGS、HGC27和MFC细胞系的细胞活性。 CEP 诱导的细胞凋亡减少了 Bcl-2 表达，并增加了 cleaved caspase 3、cleaved caspase 9、Bax 和 Bad 表达。 CEP 导致 G2 细胞周期停滞并减少细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 2 (CDK2) 的表达。同时，它增加了胃癌细胞系中的氧化应激，降低了线粒体膜电位，并增加了活性氧（ROS）的积累。从机制上讲，CEP 抑制 Kelch 样 ECH 相关蛋白 (Keap1) 表达，同时激活 NF-E2 相关因子 2 (Nrf2) 核易位，增加 Nrf2 靶基因醌氧化还原酶 1 (NQO1)、血红素加氧酶 1 (HMOX1) 和谷氨酸-半胱氨酸连接酶修饰亚基（GCLM）。此外，靶向能量代谢和RNA测序的综合分析表明，CEP可以改变D（+）-葡萄糖、D-果糖6-磷酸、柠檬酸、琥珀酸和丙酮酸等代谢物质的水平，从而改变AGS 细胞的能量代谢。此外，CEP在体内显着抑制MFC BALB/c裸鼠的肿瘤生长，与体外研究结果一致。总体而言，CEP可以通过调节Nrf2/Keap1诱导氧化应激并改变能量代谢，从而产生抗胃癌作用。我们的研究结果表明 CEP 在胃癌治疗中的潜在应用。