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  3. Synergistic and mechanistic effects of neogambogic acid in enhancing almonertinib sensitivity in non-small cell lung cancer

Synergistic and mechanistic effects of neogambogic acid in enhancing almonertinib sensitivity in non-small cell lung cancer

  • Int Immunopharmacol. 2025 Jun 26:159:114878. doi: 10.1016/j.intimp.2025.114878.
Qiqi Yang 1,  Yuan Yao 2,  Junping Wang 2,  Mengdi Pang 1,  Jinyan Wu 1,  Fusheng Yin 1,  Jun He 3,  Yanyan Wang 4,  Weidong Chen 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China.
  • 2 Center of Pharmacy, Hefei Cancer Hospital, Chinese Academy of Science, Hefei 230031,Anhui, China.
  • 3 School of Pharmacy, Anhui Xinhua University,Hefei 230088, Anhui, China.
  • 4 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China; MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, Anhui, China. Electronic address: wangyanyan@ahtcm.edu.cn.
  • 5 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China; MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei 230012, Anhui, China; Key Laboratory of Modern Traditional Chinese Medicines of Anhui Higher Education Institutes, Anhui University of Chinese Medicine, Hefei 230038, Anhui, China. Electronic address: wdchen@ahtcm.edu.cn.
PMID: 40412130 DOI: 10.1016/j.intimp.2025.114878
Abstract

Non-small cell lung Cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung Cancer by injecting Lewis cells, and evaluated the therapeutic efficacy in vivo. The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting Cancer cell Apoptosis and reducing serum tumor marker levels. In vitro experiments revealed that this combination synergistically inhibited lung Cancer cell proliferation and induced Apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing Enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/Akt signaling, leading to enhanced Apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP via PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/Akt pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.

Keywords

Almonertinib; EGFR/PI3K/AKT pathway; Gambogenic acid; Non-small cell lung cancer; Pregnane X receptor.

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