Unveiling the Novel Anti - Tumor Potential of Digitonin, a Steroidal Saponin, in Gastric Cancer: A Network Pharmacology and Experimental Validation Study.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-04-05 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S504671

Dongdong Lu, Leijie Huang, Chunyan Weng

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引用次数: 0

Abstract

Background: Gastric cancer (GC) remains a leading cause of cancer-related mortality, with limited effective treatment options for advanced stages. As a steroidal saponin with documented anti-neoplastic properties in multiple cancers, digitonin's mode of action in GC pathogenesis has yet to be fully elucidated. This research focused on exploring the potential of Digitonin in GC treatment using a combination of network pharmacology and experimental validation.

Methods: The inhibitory effects of Digitonin on the proliferation, invasion, and migration of gastric cancer cells were evaluated using CCK-8, colony formation, wound healing, and transwell assays. Key targets of Digitonin were identified through network pharmacology. Molecular docking and various experiments, including Western blot, immunofluorescence, and a subcutaneous xenograft model, were used for validation.

Results: Digitonin exhibited stronger cytotoxicity against GC cells and significantly inhibited GC cell proliferation, migration, and invasion. Network pharmacology analysis revealed that the core targets of Digitonin are involved in key cancer-related signaling pathways, including HIF-1α, Ras, and PI3K-Akt pathways, with HSP90AA1 and NFKB1 identified as central targets. Further molecular docking, Western blotting, and immunofluorescence experiments confirmed that Digitonin significantly suppressed the expression of HSP90AA1 and inhibited the nuclear translocation of NFKB1, inducing cell apoptosis. Additionally, a subcutaneous xenograft model of GC further validated that Digitonin effectively inhibited tumor growth.

Conclusion: Digitonin serves as a promising multi-target therapeutic agent for GC. This study underscores the potential of combining network pharmacology with traditional Chinese medicine to identify novel therapeutic targets and develop effective anti-cancer strategies. In addition, these findings suggest that digitonin could be a promising candidate for future clinical trials in GC treatment.

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揭示甾体皂苷洋地黄苷在胃癌中的新型抗肿瘤潜力：网络药理学和实验验证研究。

背景：胃癌（GC）仍然是癌症相关死亡的主要原因，晚期有效的治疗选择有限。作为一种甾体皂苷，地黄皂苷在多种肿瘤中具有抗肿瘤作用，但其在胃癌发病机制中的作用模式尚未完全阐明。本研究主要采用网络药理学和实验验证相结合的方法探索地黄苷在气相色谱治疗中的潜力。方法：采用CCK-8法、菌落形成法、创面愈合法和transwell法评价洋地黄苷对胃癌细胞增殖、侵袭和迁移的抑制作用。通过网络药理学方法鉴定地黄皂苷的主要作用靶点。分子对接和各种实验，包括Western blot，免疫荧光和皮下异种移植模型，用于验证。结果：洋地黄苷对胃癌细胞具有较强的细胞毒性，能明显抑制胃癌细胞的增殖、迁移和侵袭。网络药理学分析显示，Digitonin的核心靶点涉及关键的癌症相关信号通路，包括HIF-1α、Ras和PI3K-Akt通路，其中HSP90AA1和NFKB1被确定为中心靶点。进一步的分子对接、Western blotting和免疫荧光实验证实，洋地黄苷显著抑制HSP90AA1的表达，抑制NFKB1的核易位，诱导细胞凋亡。此外，GC皮下异种移植模型进一步证实了地黄皂苷能有效抑制肿瘤生长。结论：洋地黄苷是一种很有前途的多靶点胃癌治疗剂。该研究强调了将网络药理学与中医相结合，以发现新的治疗靶点和制定有效的抗癌策略的潜力。此外，这些发现表明地黄皂苷可能是未来临床试验中治疗GC的有希望的候选者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.