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

[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.