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Mechanistic studies on anticancer benzophenones from Clusiaceae fruits
In our continuing examination of polyphenolic constituents of edible fruits for anticancer activity, we have looked at a number of species in the Clusiaceae family. This family is rich in phenolic constituents, including biflavonoids, xanthones, and benzophenones. We have found that the polyisoprenylated benzophenones have good cytotoxcity in a number of colon cancer cell lines. Benzophenones are known to have anti-tumor activity, both in vitro, and in animal models, but the mechanism is unknown. We examined the effect of three Garcinia-derived benzophenones, xanthochymol, guttiferone E, and guttiferone H, on human colon cancer cells, and elucidated pathways targeted by these compounds. Three colon cancer cell lines were used, HCT116, HT29, and SW480. The IC50 concentrations were determined and the cells were then treated with xanthochymol, guttiferone E, or guttiferone H at their respective IC50 or IC50 x 2 concentrations. The effects on the cell cycle, mitochondrial membrane potential, and apoptosis were studied by flow cytometry and caspase activation assay. The changes in gene expression were assessed by Illumina 24K gene array using multiple time points. All three tested benzophenones induced G1 arrest at IC50 concentrations and caspase activation occurred at ≥IC50 concentrations. Changes in gene expression induced by benzophenone treatment were related to cell cycle arrest, protein folding, and stress response. Pathway analysis revealed that several genes, such as XBP1 and DDIT3/CHOP are part of the endoplasmic reticulum stress response. Additionally, the DDIT4/REDD1 gene, an inhibitor of the mTOR survival pathway, was up-regulated. Thus, these effects are not simply due to prooxidative effects of these compounds. The three tested benzophenones all induce growth arrest in colon cancer cells by activating the endoplasmic reticulum stress response and an inhibition of the mTOR cell survival pathway. These combined effects may contribute to the anticancer activity of these compounds.