garcinone-e and Breast-Neoplasms

Xanthones are among the most fundamental phytochemicals in nature. The anti-cancer activities of xanthones and their derivatives have been extensively studied. Recently, we found that garcinone E (GE), an effective anti-cancer phytochemical isolated from mangosteen (Garcinia mangostanal.), showed promising anti-cancer effects in vitro and in vivo. However, little is known about its effects on epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) activity.. This study aimed to identify potent dual EGFR and VEGFR2 inhibitors from mangosteen-derived xanthones using structure-activity relationship analyses.. The interaction of xanthones with EGFR and VEGFR2 was analyzed using molecular docking experiments. The kinase activities of EGFR and VEGFR2 were determined using bioluminescence assays. The rat aortic ring and Matrigel plug angiogenesis assays were used to evaluate blood vessel formation ex vivo and in vivo. A breast tumor-bearing nude mouse model was established to examine the anti-tumor effects of different xanthones.. The present study demonstrated that GE was the most potent dual inhibitor of EGFR and VEGFR2 among all xanthones tested. These findings may provide valuable information for the future development of novel and effective dual inhibitors of EGFR and VEGFR2.

Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Cell Proliferation; ErbB Receptors; Female; Garcinia mangostana; Humans; Mice; Molecular Docking Simulation; Neovascularization, Pathologic; Rats; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xanthones; Zebrafish

Cancer metastasis remains the most common cause of death in breast cancer patients. Tumor-associated macrophages (TAMs) are a novel therapeutic target for the treatment of metastatic breast cancer. Despite the good anti-cancer activity of garcinone E (GE), there are no reports on its therapeutic effects on breast cancer metastasis. The objective of this study was to examine the anti-cancer effects of GE on metastatic breast cancer. RAW 264.7 and THP-1 cells were polarized to M2 macrophages by IL-4/IL-13 in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were used to explore the effect of GE on breast cancer growth and metastasis in vivo. In vitro studies showed that GE dose-dependently suppressed IL-4 + IL-13-induced expression of CD206 in both RAW 264.7 cells and differentiated THP-1 macrophages. However, GE did not affect the LPS + IFN-γ-induced polarization to the M1-like macrophages in vitro. GE inhibited the expression of the M2 macrophage specific genes in RAW 264.7 cells, and simultaneously impaired M2 macrophage-induced breast cancer cell proliferation and migration, and angiogenesis. In animal studies, GE significantly suppressed tumor growth, angiogenesis, and lung metastasis in 4T1 tumor-bearing mice, without causing toxicity. In both tumor and lung tissues, the proportion of M2-like TAMs was significantly decreased while the proportion of M1-like TAMs was markedly increased by GE treatment. Mechanistically, GE inhibited phosphorylation of STAT6 in vitro and in vivo. Our results demonstrate for the first time that GE suppresses breast cancer growth and pulmonary metastasis by modulating M2-like macrophage polarization through the STAT6 signaling pathway.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Interleukin-13; Interleukin-4; Mice; Signal Transduction; STAT6 Transcription Factor; Tumor-Associated Macrophages