Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou 730000, China.
College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China.
Int Immunopharmacol. 2024 Jun 15;134:112245. doi: 10.1016/j.intimp.2024.112245. Epub 2024 May 14.
Gastric cancer (GC) has posed a great threat to the lives of people around the world. To date, safer and more cost-effective therapy for GC is lacking. Traditional Chinese medicine (TCM) may provide some new options for this. Guiqi Baizhu Formula (GQBZF), a classic TCM formula, has been extensively used to treat GC, while its bioactive components and therapeutic mechanisms remain unclear. In this study, we evaluated the underlying mechanisms of GQBZF in treating GC by integrative approach of chemical bioinformatics. GQBZF lyophilized powder (0.0625 mg/mL, 0.125 mg/mL) significantly attenuated the expression of p-IGF1R, PI3K, p-PDK1, p-VEGFR2 to inhibit the proliferation, migration and induce apoptosis of gastric cancer cells, which was consistent with the network pharmacology. Additionally, atractylenolide Ⅰ, quercetin, glycyrol, physcione and aloe-emodin, emodin, kaempferol, licoflavone A were found to be the key compounds of GQBZF regulating IGF1R and VEGFR2, respectively. And among which, glycyrol and emodin were determined as key active compounds against GC by farther vitro experiments and LC/MS. Meanwhile, we also found that glycyrol inhibited MKN-45 cells proliferation and enhanced apoptosis, which might be related to the inhibition of IGF1R/PI3K/PDK1, and emodin could significantly attenuate the MKN-45 cells migration, which might be related to the inhibition of VEGFR2-related signaling pathway. These results were verified again by molecular dynamics simulation and binding interaction pattern. In summary, this study suggested that GQBZF and its key active components (glycyrol and emodin) can suppress IGF1R/PI3K/PDK1 and VEGFR2-related signaling pathway, thereby inhibiting tumor cell proliferation and migration and inducing apoptosis. These findings provided an important strategy for developing new agents and facilitated clinical use of GQBZF against GC.
胃癌（GC）已对全球人民的生命健康构成了严重威胁。迄今为止，GC 仍然缺乏更安全、更具成本效益的治疗方法。传统中药（TCM）可能为此提供一些新的选择。归芪白术方（GQBZF）是一种经典的 TCM 方剂，已广泛用于治疗 GC，但其生物活性成分和治疗机制尚不清楚。在这项研究中，我们通过化学生物信息学的综合方法评估了 GQBZF 治疗 GC 的潜在机制。GQBZF 冻干粉末（0.0625mg/mL，0.125mg/mL）显著降低了 p-IGF1R、PI3K、p-PDK1、p-VEGFR2 的表达，从而抑制胃癌细胞的增殖、迁移并诱导其凋亡，这与网络药理学一致。此外，还发现阿魏酸、槲皮素、甘草醇、京尼平苷元和大黄素、大黄素、山柰酚、甘草素 A 分别是 GQBZF 调节 IGF1R 和 VEGFR2 的关键化合物。其中，通过进一步的体外实验和 LC/MS 确定甘草醇和大黄素是 GQBZF 治疗 GC 的关键活性化合物。同时，我们还发现甘草醇抑制 MKN-45 细胞增殖并增强其凋亡，这可能与抑制 IGF1R/PI3K/PDK1 有关，而大黄素能显著抑制 MKN-45 细胞迁移，这可能与抑制 VEGFR2 相关信号通路有关。这些结果通过分子动力学模拟和结合相互作用模式再次得到验证。综上所述，本研究表明 GQBZF 及其关键活性成分（甘草醇和大黄素）可抑制 IGF1R/PI3K/PDK1 和 VEGFR2 相关信号通路，从而抑制肿瘤细胞增殖和迁移并诱导其凋亡。这些发现为开发新的药物提供了重要策略，并促进了 GQBZF 在 GC 治疗中的临床应用。
