Chinese agarwood petroleum ether extract suppressed gastric cancer progression via up-regulation of DNA damage-induced G0/G1 phase arrest and HO-1-mediated ferroptosis

IF 7.5 2区医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE

Chinese Journal of Natural Medicines Pub Date : 2025-10-01 Epub Date: 2025-10-08 DOI:10.1016/S1875-5364(25)60876-4

Lishan Ouyang , Xuejiao Wei , Fei Wang , Huiming Huang , Xinyu Qiu , Zhuguo Wang , Peng Tan , Yufeng Gao , Ruoxin Zhang , Jun Li , Zhongdong Hu

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引用次数: 0

Abstract

Gastric cancer (GC) is characterized by high morbidity and mortality rates. Chinese agarwood comprises the resin-containing wood of Aquilaria sinensis (Lour.) Gilg., traditionally utilized for treating asthma, cardiac ischemia, and tumors. However, comprehensive research regarding its anti-GC effects and underlying mechanisms remains limited. In this study, Chinese agarwood petroleum ether extract (CAPEE) demonstrated potent cytotoxicity against human GC cells, with half maximal inhibitory concentration (IC₅₀) values for AGS, HGC27, and MGC803 cells of 2.89, 2.46, and 2.37 μg·mL⁻¹, respectively, at 48 h. CAPEE significantly induced apoptosis in these GC cells, with B-cell lymphoma-2 (BCL-2) associated X protein (BAX)/BCL-2 antagonist killer 1 (BAK) likely mediating CAPEE-induced apoptosis. Furthermore, CAPEE induced G₀/G₁ phase cell cycle arrest in human GC cells via activation of the deoxyribonucleic acid (DNA) damage-p21-cyclin D1/cyclin-dependent kinase 4 (CDK4) signaling axis, and increased Fe²⁺, lipid peroxides and reactive oxygen species (ROS) levels, thereby inducing ferroptosis. Ribonucleic acid (RNA) sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting analyses revealed CAPEE-mediated upregulation of heme oxygenase-1 (HO-1) in human GC cells. RNA interference studies demonstrated that HO-1 knockdown reduced CAPEE sensitivity and inhibited CAPEE-induced ferroptosis in human GC cells. Additionally, CAPEE administration exhibited robust in vivo anti-GC activity without significant toxicity in nude mice while inhibiting tumor cell growth and promoting apoptosis in tumor tissues. These findings indicate that CAPEE suppresses human GC cell growth through upregulation of the DNA damage-p21-cyclin D1/CDK4 signaling axis and HO-1-mediated ferroptosis, suggesting its potential as a candidate drug for GC treatment.

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沉香石油醚提取物通过上调DNA损伤诱导的G0/G1期阻滞和ho -1介导的铁下垂抑制胃癌进展

胃癌（GC）具有高发病率和高死亡率的特点。沉香由沉香木（Aquilaria sinensis, Lour.）的含树脂木材组成。Gilg。传统上用于治疗哮喘、心脏缺血和肿瘤。然而，关于其抗gc作用及其机制的全面研究仍然有限。在本研究中，沉香油醚提取物（CAPEE）对人胃癌细胞表现出强大的细胞毒性，48 h时对AGS、HGC27和MGC803细胞的半数最大抑制浓度（IC50）分别为2.89、2.46和2.37 μg·mL−1。CAPEE显著诱导这些胃癌细胞凋亡，其中b细胞淋巴细胞2 （BCL-2）相关X蛋白(BAX)/BCL-2拮抗剂杀伤1 （BAK）可能介导了CAPEE诱导的凋亡。此外，CAPEE通过激活脱氧核糖核酸（DNA）损伤-p21-cyclin D1/cyclin依赖性激酶4 （CDK4）信号轴，诱导人GC细胞G0/G1期细胞周期阻滞，增加Fe2+、脂质过氧化物和活性氧（ROS）水平，从而诱导铁死亡。核糖核酸（RNA）测序、实时定量聚合酶链反应（RT-qPCR）和Western blotting分析显示，capee介导的血红素加氧酶-1 （HO-1）在人GC细胞中上调。RNA干扰研究表明，HO-1敲低可降低CAPEE敏感性并抑制CAPEE诱导的人GC细胞铁下垂。此外，CAPEE在裸鼠体内表现出强大的抗gc活性，无明显毒性，同时抑制肿瘤细胞生长，促进肿瘤组织凋亡。这些发现表明，CAPEE通过上调DNA损伤-p21-cyclin D1/CDK4信号轴和ho -1介导的铁凋亡来抑制人GC细胞的生长，表明其作为GC治疗的候选药物的潜力。

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来源期刊

Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY

CiteScore

7.50

自引率

4.30%

发文量

2235

期刊介绍： The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.