title: Novel small molecule drugs inhibit tumor cell metabolism and show potent anti-tumorigenic potential.
abstract: BACKGROUND
  Rapidly dividing tumor cells have an increased demand for nutrients to support their characteristic unabated growth; this demand is met by an increased availability of nutrients such as amino acids through vasculogenesis and by the enhanced cellular entry of nutrients through the upregulation of specific transporters. Deprivation of intracellular amino acids or block of amino acid uptake has been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft models.
  
  
  RESULTS
  In this paper, we provide evidence that the two small molecule oxyphenisatine analogs TOP001 and TOP216 exert their anti-cancer effect by affecting tumor cell metabolism and inducing intracellular amino acid deprivation, leading to a block of cell proliferation. GCN2-mediated phosphorylation of eIF2α as well as mTOR pathway inhibition supports the above notion. In addition, these novel anti-cancer compounds inhibit DNA and protein synthesis and induce apoptosis in a broad spectrum of cancer cell lines. In vivo, the compounds induce tumor stasis and regression in mouse xenograft models of human breast, prostate, ovarian and pancreatic cancer, both when administered intravenously and orally.
  
  
  CONCLUSIONS
  In conclusion, these small molecules, built on a 1,3-dihydroindole-2-one scaffold, elicit strong anti-proliferative and cytotoxic activity, and importantly, a strong anti-tumorigenicity is observed in in vivo xenograft models of human breast, ovary, prostate and pancreatic cancers encouraging the translation of this class of compounds into the clinic.
authors.affiliation: XPU Bartholin, Rigshospitalet 3731, TopoTarget A/S, Copenhagen Biocenter, Ole Maaløesvej 5, 2200 Copenhagen, Denmark. chh@topotarget.com
authors.forename: Christina
authors.initials: C
authors.lastname: Trojel-Hansen
authors.forename: Kamille Dumong
authors.initials: KD
authors.lastname: Erichsen
authors.forename: Mette Knak
authors.initials: MK
authors.lastname: Christensen
authors.forename: Peter Buhl
authors.initials: PB
authors.lastname: Jensen
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Søren Jensby
authors.initials: SJ
authors.lastname: Nielsen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010114:Oxyphenisatin Acetate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; C560641:Top001 compound; C560642:Top216 compound; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D020169:Caspases; D010114:Oxyphenisatin Acetate