title: Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy.
abstract: BACKGROUND
  Environmental conditions or chemical agents can interfere with the function of the endoplasmic reticulum, and the resulting endoplasmic reticulum (ER) stress can be toxic to the cell if it is not relieved. The classical compensatory response to ER stress is the unfolded protein response (UPR) that reduces protein load in the ER. However, autophagy may also compensate by removing large insoluble protein aggregates. Agents that stress the ER can have anti-cancer activity, and novel applications of ER stress inducing agents are being investigated. Plant stilbenes are a class of stress responsive molecules that includes resveratrol, which are being investigated as potential therapeutics in humans for conditions such as aging or cancer.
  
  
  RESULTS
  We performed a screen of 1726 small, drug like molecules to identify those that could activate an ER-stress responsive luciferase gene. After secondary screening, we determined that the plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group. ER stress can be particularly toxic to cells with high ER load, so we examined their effect on cells expressing the Wnt family of secreted glycoprotein growth factors. Molecular analysis determined that these ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16. Combining pterostilbene (to induce ER stress) with chloroquine (to inhibit autophagy) lead to significant cellular toxicity in cells from aggressive acute lymphoblastic leukemia.
  
  
  CONCLUSIONS
  Plant stilbenes are potent inducers of ER stress. However, their toxicity is more pronounced in cancer cells expressing Wnt growth factors. The toxicity of stilbenes in these ALL cells can be potentiated by the addition of autophagy inhibitors, suggesting a possible therapeutic application.
authors.affiliation: Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. Electronic address: Ioanna.papandreou@osumc.edu.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.affiliation: Department of General Biology, University of Patras, Rio, Greece. Electronic address: mverras@upatras.gr.
authors.forename: Meletios
authors.initials: M
authors.lastname: Verras
authors.affiliation: Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. Electronic address: betina.mcneil@osumc.edu.
authors.forename: Betina
authors.initials: B
authors.lastname: McNeil
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: albert.koong@stanford.edu.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.affiliation: Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. Electronic address: Nicholas.denko@osumc.edu.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D010944:Plants / Q000737:chemistry*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D000077185:Resveratrol; D054852:Small Molecule Libraries / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D000975:Antioxidants; D054852:Small Molecule Libraries; D013267:Stilbenes; C107773:pterostilbene; C041525:3,3',4,5'-tetrahydroxystilbene; D002738:Chloroquine; D000077185:Resveratrol
keywords: High throughput screen; Stilbenes; Stress responses; Unfolded Protein Response; Wnt growth factors