title: 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 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.
authors.affiliation: Division of Gastroenterology, University of Connecticut Health Center, Farmington, CT 06030-2817, USA. protiva@uchc.edu
authors.forename: Petr
authors.initials: P
authors.lastname: Protiva
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hopkins
authors.forename: Scott
authors.initials: S
authors.lastname: Baggett
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Martin
authors.initials: M
authors.lastname: Lipkin
authors.forename: Peter R
authors.initials: PR
authors.lastname: Holt
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kennelly
authors.forename: Weinstein I
authors.initials: WI
authors.lastname: Bernard
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000378:metabolism / Q000494:pharmacology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D029760:Garcinia; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D016014:Linear Models; D051336:Mitochondrial Membranes / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D054876:Prenylation; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: C497109:ATF4 protein, human; D001577:Benzophenones; C497249:DDIT3 protein, human; C469991:DDIT4 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C499940:guttiferone H; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C414432:xanthochymol; C414433:guttiferone E; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020169:Caspases