Xin Pengfei, Wang Shirui, Xu Xin, Liu Qingmei, Zhang Caifeng
Department of Stomatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Heliyon. 2023 Jun 7;9(6):e17080. doi: 10.1016/j.heliyon.2023.e17080. eCollection 2023 Jun.
Non-small-cell lung cancer (NSCLC) is a major public health concern with a high incidence worldwide. Coal-derived fulvic acids (FAs) contain functional groups in their chemical structures. Overexpression of cyclooxygenases-2 (COX-2), prostaglandin E2 (PGE2), and the PGE2 receptor EP4 subtype (EP4) can have a potential link with the increased tumor incidence and promoted tumor growth and metastasis in NSCLC. This study aimed to assess the biological roles of coal-derived FAs in the growth and development of NSCLC and to elucidate the underlying molecular mechanisms.
A web-based tool for predicting small-molecule pharmacokinetics (pkCSM) was used to analyze the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of FAs. Molecular docking and dynamic simulations were performed to analyze the binding affinities of COX-2 and EP4 to FA. An acute toxicity test and an antitumor study were used to analyze the toxicity and anti-NSCLC effects of FAs. Thirty NSCLC-bearing nude mice were randomly divided into five groups (six mice per group): vehicle control, positive control with 20 mg/kg body weight (BW) 5-fluorouracil, and three treatments with 25, 50, and 100 mg/kg BW FAs. The BW and tumor volume were recorded, and the COX-2, PGE2, and EP4 protein expression were measured and analyzed.
Using the predictive pkCSM algorithm, we found that FA did not cause developmental toxicity. Molecular simulations revealed that COX-2 and EP4 expression was inhibited by FA. An acute toxicity test conformed that the maximum tolerated FAs dose was >3.0 g/kg BW. The animal study demonstrated that FA treatment significantly downregulated the expression of COX-2, PGE2, and EP4 in NSCLC-bearing mice compared to that in vehicle control mice (p < 0.01).
Natural FAs may exert anti-NSCLC effects through the COX-2/PGE2/EP4 axis.
非小细胞肺癌（NSCLC）是一个重大的公共卫生问题，在全球范围内发病率很高。煤衍生的富里酸（FAs）在其化学结构中含有官能团。环氧合酶-2（COX-2）、前列腺素E2（PGE2）和PGE2受体EP4亚型（EP4）的过表达可能与NSCLC中肿瘤发生率增加以及肿瘤生长和转移促进存在潜在联系。本研究旨在评估煤衍生的FAs在NSCLC生长和发展中的生物学作用，并阐明其潜在的分子机制。
使用基于网络的小分子药代动力学预测工具（pkCSM）来分析FAs的吸收、分布、代谢、排泄和毒性（ADMET）特性。进行分子对接和动力学模拟以分析COX-2和EP4与FA的结合亲和力。采用急性毒性试验和抗肿瘤研究来分析FAs的毒性和抗NSCLC作用。将30只荷NSCLC裸鼠随机分为五组（每组6只）：溶剂对照组、20mg/kg体重（BW）5-氟尿嘧啶阳性对照组以及25、50和100mg/kg BW FAs的三个处理组。记录体重和肿瘤体积，并测量和分析COX-2、PGE2和EP4蛋白表达。
使用预测性pkCSM算法，我们发现FA不会引起发育毒性。分子模拟显示COX-2和EP4的表达受到FA抑制。急性毒性试验证实FA的最大耐受剂量>3.0g/kg BW。动物研究表明，与溶剂对照组小鼠相比，FA处理显著下调了荷NSCLC小鼠中COX-2、PGE2和EP4的表达（p<0.01）。
天然FAs可能通过COX-2/PGE2/EP4轴发挥抗NSCLC作用。
