Purpose: ACT001 is a novel sesquiterpene lactone derivative with anticancer effects, including the reversal of tamoxifen resistance in estrogen receptor-positive breast cancer cells. However, few studies have investigated the anticancer effects of ACT001 in triple-negative breast cancer (TNBC), a highly aggressive cancer with a poor prognosis. This study aimed to investigate the effects of ACT001 on TNBC and the potential mechanism underlying these effects.
Materials and Methods: The anticancer effects of ACT001 on the murine TNBC cell line 4T1 were evaluated by Cell Counting Kit-8 assay, animal experiments, TUNEL staining, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, and Western blotting analysis.
Results: ACT001 induced apoptosis in 4T1 cells by upregulating B cell lymphoma 2-associated X protein expression. Moreover, ACT001 markedly decreased levels of secretory granulocyte-macrophage colony stimulating factor (GM-CSF) in 4T1 tumors, decreased the number of myeloid-derived suppressor cells (MDSCs), and reduced angiogenesis. Furthermore, GM-CSF promoted angiogenesis and the proliferation of MDSCs in a dose-dependent manner. Finally, ACT001 suppressed phospho-NF-κB and IκB-α levels in 4T1 cells, thereby further decreasing GM-CSF levels.
Conclusion: Our results suggest that ACT001 exerts its anticancer effects by inducing apoptosis in murine TNBC cell line 4T1 and regulates the tumor microenvironment by attenuating angiogenesis and accumulation of MDSCs in 4T1 tumors. The underlying mechanism may involve the suppression of NF-κB activity.
Keywords: ACT001, triple-negative breast cancer, myeloid-derived suppressor cells, angiogenesis, NF-κB