Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response

Abstract

Polyisoprenylated benzophenones derived from Garcinia xanthochymus have cytotoxic activity in vitro and antitumor activity in rodent models, but the mechanism is unknown. The purpose of our study was to examine in parallel molecular pathways that are targeted by 3 Garcinia-derived benzophenones-xanthochymol (X), guttiferone E (GE) and guttiferone H (GH), in 3 human colon cancer cell lines, HCT116, HT29 and SW480. The IC50 concentrations were determined and the cells were then treated with X, GE or GH at their respective IC50 or IC50x2 concentrations. Effects on the cell cycle, mitochondrial membrane potential and apoptosis were assessed by flow cytometry and caspase activation. Changes in gene expression were assessed with Illumina 24 K gene arrays. We found that X, GE and GH induced loss of mitochondrial membrane potential and G1 arrest at their IC50 concentrations and induced caspase activation at IC50 3 2 concentrations. An analysis of the changes in gene expression revealed that with all 3 compounds and all 3 cell lines there was a marked increase in expression of several genes, including XBP1, ATF4 and DDIT3/CHOP, which are components of the endoplasmic reticulum stress response. The DDIT4/REDD1 gene, an inhibitor of the mTOR survival pathway, was also up-regulated. Therefore, X, GE and GH appear to inhibit the growth of human colon cancer cells, at least in part, by activating the endoplasmic reticulum stress response and inhibiting the mTOR cell survival pathway. These combined effects may contribute to the anticancer activity of these novel compounds.

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

“…Polyisoprenylated benzophenones inhibited growth of human colon cancer cells by the activation of DDIT3, ATF4, and XBP1 genes and inhibition of mTOR cell survival pathway through over-expression of DDIT4 gene (Protiva et al 2008). In a recent report, DDIT3 induction has been also associated with up-regulation of DR5 and subsequent apoptosis in human colon carcinoma HT29 cells following treatment with the polyphenol rottlerin (Lim et al 2009).…”

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

“…Specifically, IFNg production was higher by the CM CTL population in response to breast cancer (MDA-MB-231: 76.8% CM vs. 17 EM; PL45: 52.0% CM vs. 4% EM) cells (Fig. 6C).…”

“…6 Genome-wide profiling, along with association studies and immunohistochemistry, demonstrated that XBP1 expression was induced in a variety of primary cancers or cancer cell lines including hematological malignancies such as multiple myeloma and acute lymphoblastic leukemias, [7][8][9] as well as breast cancers, 10,11 hepatocellular carcinoma, 12,13 pancreatic adenocarcinomas, 14,15 and colon cancer. 16,17 It has been demonstrated that XBP1 is activated in primary mammary tumors, and that its expression correlates with enhanced tumor growth. 18 In support of a direct role for XBP1 in tumorigenesis, the loss of XBP1 was shown to severely inhibit tumor growth.…”

Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms

“…5). Cell death resulting from xanthochymol treatment of C. albicans appeared to be similar to its caspase-dependent apoptotic effects in human cancer cells (15,16,29,39). Xanthochymol-treated biofilms showed externalization of PS and DNA cleavage, as evidenced by TUNEL fluorescence (Fig.…”

“…Investigations in mammalian model systems have established apoptosis and growth arrest as a result of xanthochymol intervention (16,29). We therefore hypothesized that the observed cell death in our biofilms may be apoptotic in nature.…”