title: Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract.
abstract: BACKGROUND
  Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound.
  
  
  METHODS
  The IC50 values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 μmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD(+) ratio were measured.
  
  
  RESULTS
  The mean IC50 value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 μmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD(+) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy.
  
  
  CONCLUSIONS
  FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism.
authors.affiliation: Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany. Otto_c@ukw.de.|Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany. Otto_c@ukw.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Otto
authors.affiliation: Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.|Present Address: Spital Bülach, Medizinische Klinik, Spitalstrasse 24, 8180, Bülach, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Hahlbrock
authors.affiliation: Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.|Present Address: Missionsärztliche Klinik, Fachabteilung Urologie, Salvatorstraße 7, 97074, Würzburg, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Eich
authors.affiliation: Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.|Present Address: Klinik für Allgemein-, Viszeral-, Gefäß- und Thoraxchirurgie, Krankenhaus Leopoldina der Stadt Schweinfurt, Gustav-Adolf-Straße 8, 97422, Schweinfurt, Germany.
authors.forename: Ferdi
authors.initials: F
authors.lastname: Karaaslan
authors.affiliation: Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Jürgens
authors.affiliation: Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.
authors.forename: Christoph-Thomas
authors.initials: CT
authors.lastname: Germer
authors.affiliation: Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.|Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, University of Würzburg, D-97070, Würzburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Wiegering
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital of Würzburg, Josef-Schneider-Str. 4, D-97080, Würzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kämmerer
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005285:Fermentation; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology*; D014908:Triticum / Q000737:chemistry*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D010936:Plant Extracts; C030511:2,6-dimethoxy-1,4-benzoquinone
keywords: Autophagy; Benzoquinone; Cancer cells; Cytostatic; Cytotoxicity; FWGE; Reactive oxygen species