Naturally derived Erythrinin C targets γ-secretase signaling to suppress triple-negative breast cancer progression and reverse paclitaxel resistance

  • Phytomedicine. 2026 May:154:158016. doi: 10.1016/j.phymed.2026.158016.
Ke-Fan Yang  1 ,  Di Wang  2 ,  Kuo Yao  1 ,  Ran Xu  1 ,  Li-Zhi Hu  1 ,  Yue-Yang Liu  3 ,  Lu Zhang  4 ,  Qian Xu  5 ,  Xin Yang  6 ,  Ming-Sheng Zhou  7 ,  Hui Jia  8
Affiliations
  • 1. Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang 110034, China.
  • 2. Department of Pathology, General Hospital of Northern Theater Command, Shenyang 110015, China.
  • 3. Science and Experimental Research Center of Shenyang Medical College, No 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, China.
  • 4. Science and Experimental Research Center of Shenyang Medical College, No 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, China. Electronic address: [email protected].
  • 5. Science and Experimental Research Center of Shenyang Medical College, No 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, China. Electronic address: [email protected].
  • 6. Department of Endocrinology, General Hospital of Northern Theater Command, Shenyang 110015, China. Electronic address: [email protected].
  • 7. Science and Experimental Research Center of Shenyang Medical College, No 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, China. Electronic address: [email protected].
  • 8. School of Traditional Chinese Medicine, Shenyang Medical College, No 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, China. Electronic address: [email protected].
PMID: 41771210 DOI: 10.1016/j.phymed.2026.158016
Abstract

Background: Triple-negative breast Cancer (TNBC) is a highly aggressive subtype of breast Cancer. Paclitaxel (Taxol) serves as a first-line chemotherapeutic agent, but the emergence of drug resistance often limits its clinical efficacy. Bioactive compounds with Anticancer potential and reduced toxicity have thus gained increasing research interest. Erythrinin C (EC), known for its favorable drug-like properties and accessible sourcing has attracted significant attention. However, its mechanism of action and role in modulating chemotherapy resistance remain unclear.

Purpose: This study aimed to evaluate the antitumor effects of EC on TNBC both in vivo and in vitro, and to investigate its ability to reverse of drug resistance in TNBC/Taxol cells either alone or in combination with Taxol.

Methods: The crystal structure of the γ-secretase protein was obtained from the Protein Data Bank (RCSB PDB), and a pharmacophore model was constructed based on its natural small-molecule ligands. Pharmacophore-based screening was performed across traditional Chinese medicine and natural product database to identify potential drug candidates. Confirm the interaction target between EC and γ-secretase was validated, and the biological effects, genetic influences, and in vivo activity of EC targeting γ-secretase were assessed through in vitro and in vivo experiments.

Results: EC was identified as a γ-secretase Inhibitor and was shown to suppress TNBC cell proliferation and migration in vitro. Genetic modulation of PSEN-1 in MDA-MB-231 cells revealed that low PSEN-1 expression inhibits the malignant phenotype of TNBC cells. Pharmacological evaluation confirmed that EC treatment effectively slows TNBC progression. Furthermore, EC effectively reversed Taxol resistance in TNBC/Taxol cells. In vivo experiments further demonstrated that the combination of EC and Taxol significantly inhibited xenograft tumor growth.

Conclusion: EC acts as a natural γ-secretase Inhibitor that exerts significant anti-TNBC activity in both in vitro and in vivo by targeting PSEN-1 subunit. It also reverses TNBC/Taxol resistance at both cellular and animal levels, highlighting its promising and potential as a novel targeted therapeutic candidate for TNBC.

Keywords
Erythrinin C; Paclitaxel resistance; Triple-negative breast cancer; γ-secretase inhibitor.
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