guttiferone-e and Colonic-Neoplasms

The emergence of drug-resistant cancer cells drastically reduces the efficacy of many antineoplasic agents and, consequently, increases the frequency of therapeutic failure. Benzophenones are known to display many pharmacological properties including cytotoxic activities. The present study was aimed at investigating the cytotoxicity and the modes of action of four naturally occurring benzophenones 2,2',5,6'-tetrahydroxybenzophenone (1), isogarcinol (2), isoxanthochymol (3) and guttiferone E (4) on a panel of eleven cancer cell lines including various sensitive and drug-resistant phenotypes.. The cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 2-4. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS).. The four tested benzophenones inhibited the proliferation of all tested cancer cell lines including sensitive and drug-resistant phenotypes. Collateral sensitivity of cancer cells to compounds 1-4 was generally better than to doxorubicin. Compound 2 showed the best activity with IC50 values below or around 1 μM against HCT116 colon carcinoma cells (p53+/+) (0.86 μM) and leukemia CCRF-CEM (1.38 μM) cell lines. Compounds 2-4 strongly induced apoptosis in CCRF-CEM cells via caspases 3/7, caspase 8 and caspase 9 activation and disruption of MMP.. The studied benzophenones are cytotoxic compounds that deserve more detailed exploration in the future, to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzophenones; Carcinoma; Caspases; Cell Proliferation; Colonic Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; HCT116 Cells; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia; Matrix Metalloproteinases; Neoplasms; Phenotype; Phytotherapy; Plant Extracts; Reactive Oxygen Species

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 x 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.

Topics: Activating Transcription Factor 4; Apoptosis; Benzophenones; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; DNA-Binding Proteins; Endoplasmic Reticulum; Garcinia; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Inhibitory Concentration 50; Linear Models; Mitochondrial Membranes; Nuclear Proteins; Prenylation; Protein Kinases; Reactive Oxygen Species; Regulatory Factor X Transcription Factors; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factor CHOP; Transcription Factors; Up-Regulation; X-Box Binding Protein 1