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Compound 17 Inhibits Lung Cancer Progression via Inducing Cellular Apoptosis and Blocking TNF Signaling Pathway
Jiexin Zhang1, Yunya Zhang1, Yaru Zhao1
1College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
Abstract:
Lung cancer ranks among the most commonly diagnosed malignancies worldwide, with dismal prognosis largely due to its intrinsic drug resistance and high recurrence rate. Herein, we synthesized 30 glycyrrhetinic acid derivatives and evaluated their anti-lung cancer potential both in vitro and in vivo. The biological effects of compound 17 on A549 cells were determined using MTT, colony formation, and Transwell assays. Flow cytometry, transcriptomic profiling, and RT-qPCR were performed to identify differentially expressed genes, followed by GO and KEGG enrichment analyses and molecular docking validation. A mouse xenograft tumor model was employed to assess therapeutic efficacy and systemic toxicity. Compound 17 exhibited dose-dependent inhibition of A549 cell proliferation, migration, and invasion, achieving an IC50 value of 0.6011 ± 0.05 μM. It induced G1-phase cell cycle arrest and apoptosis by inhibiting the TNF signaling pathway and modulating apoptosis-related proteins. In vivo experiments demonstrated that compound 17 exerted a tumor inhibition rate of 80.61% without observable toxic side effects. This study is the first to demonstrate that compound 17 exerts potent anti-lung cancer activity by targeting the TNF signaling pathway and activating the mitochondrial apoptosis pathway, providing a critical experimental foundation for its development as a novel therapeutic agent against lung cancer.
Insights
A novel glycyrrhetinic acid derivative, compound 17, shows significant promise in fighting lung cancer. It effectively inhibits tumor growth and induces cancer cell death by targeting key cellular pathways, offering a potential new therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Lung cancer is a leading cause of cancer death globally, characterized by drug resistance and recurrence.
- Developing novel therapeutic agents with improved efficacy and reduced toxicity is crucial for improving patient outcomes.
Purpose of the Study:
- To synthesize and evaluate novel glycyrrhetinic acid derivatives for anti-lung cancer activity.
- To investigate the mechanism of action of the most potent compound, identified as compound 17.
Main Methods:
- Synthesis of 30 glycyrrhetinic acid derivatives.
- In vitro assays (MTT, colony formation, Transwell) on A549 lung cancer cells.
- Flow cytometry, transcriptomic profiling, RT-qPCR, GO/KEGG analysis, and molecular docking.
- In vivo mouse xenograft model to assess efficacy and toxicity.
Main Results:
- Compound 17 demonstrated potent dose-dependent inhibition of A549 cell proliferation, migration, and invasion (IC50 = 0.6011 ± 0.05 μM).
- Compound 17 induced G1-phase cell cycle arrest and apoptosis via TNF signaling pathway inhibition and modulation of apoptosis-related proteins.
- In vivo studies showed an 80.61% tumor inhibition rate with no observable toxicity.
Conclusions:
- Compound 17 exhibits significant anti-lung cancer potential through targeting the TNF signaling pathway and activating mitochondrial apoptosis.
- This study provides a strong foundation for the development of compound 17 as a novel therapeutic agent for lung cancer treatment.
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