Polycyclic polyprenylated acylphloroglucinols from Garcinia xanthochymus fruits exhibit antitumor effects by inhibition of STAT3 signaling pathway
The fruits of Garcinia xanthochymus can be eaten raw and processed into jams, preserves and vinegar. It provides not only vitamin and protein nutrient, but also pharmacologically active compounds, among which, polycyclic polyprenylated acylphloroglucinols (PPAPs) are a major class. According to the literature, PPAPs had good anti-cancer effects. This study investigated the antitumor effects and mechanism of S1 (the mixture regioisomers of xanthochymol and guttiferone E) and S2 (the mixture regioisomers of isoxanthochymol and cycloxanthochymol) isolated from the fruits of G. xanthochymus. In H22 allograft mice model, S1 and S2 could suppress the liver tumor growth and phosphorylation of STAT3. Computational modeling showed that S1 and S2 could form hydrogen bands with SH2 domain of STAT3. In HepG2 and MCF-7 cell lines, S1 and S2 downregulated the expression of p-STAT3Tyr705. Moreover, S1 and S2 inhibited the phosphorylation of JAK2 and Src, which are the upstream kinases of STAT3, and the expression of various STAT3-regulated genes, including anti-apoptotic (Bcl-XL, Mcl-1 and survivin), proliferative (cyclin D1) and angiogenic (VEGF) genes. As a result, S1 and S2 arrested the cell cycle and induced the cell apoptosis, which were proved by the activation of cleaved caspase-3 and caspase-8. These results demonstrated that the S1 and S2 from G. xanthochymus had antitumor effects through the inactivation of STAT3, and could be promising candidate for cancer treatment.