Garcinone C Suppresses Cancer Stem Cells and Induces Apoptosis in Triple-Negative Breast Cancer Through Canonical Wnt Signaling

Natural phytochemicals derived from dietary sources have demonstrated promising anticancer potential with favorable safety profiles. Among them, Garcinone C (Gar. C), a xanthone derived from mangosteen (Garcinia mangostana), demonstrated superior antitumor activity compared to other derivatives in our preliminary screening. Here, we report the first comprehensive evaluation of the efficacy of Gar. C against triple-negative breast cancer (TNBC) using both in vitro and in vivo models. Gar. C significantly inhibited cell viability and stemness in TNBC cell lines (SUM159 and SUM149) in a dose-dependent manner, with IC₅₀ values of 4.54 ± 0.13 µM and 5.97 ± 0.16 µM, respectively. Mechanistically, Gar. C induced mitochondrial-mediated apoptosis, as indicated by an increased Bax/Bcl-2 ratio and loss of mitochondrial membrane potential, and triggered G₀/G₁ cell cycle arrest via modulation of cyclin D1 and p21. Furthermore, Gar. C effectively suppressed cancer stemness, as evidenced by a reduced CD44⁺/CD24⁻ population. RNA sequencing and Western blot analyses suggested that the inhibition of the Wnt/β-catenin signaling pathway was a key mechanism contributing to its dual effects on inducing apoptosis and suppressing stemness. Importantly, in a xenograft mouse model using SUM159 cells, Gar. C significantly inhibited tumor growth and metastasis. These findings highlight the potential of Gar. C as a promising natural compound for the prevention and treatment of TNBC.