title: Triethylenetetramine modulates polyamine and energy metabolism and inhibits cancer cell proliferation.
abstract: Polyamine metabolism is an attractive anticancer drug target, since polyamines are absolutely required for cellular proliferation, and increased levels of polyamines and their biosynthetic enzyme ornithine decarboxylase (ODC) are associated with cancer. Triethylenetetramine (TETA) is a charge-deficient isosteric analogue of the polyamine spermidine (Spd) and a Cu(II)-chelating compound used for the treatment of Wilson's disease, and it has been implicated as a potential anticancer therapeutic drug. In the present study, we studied the effects of TETA in comparison with two other Cu(II)-chelators, D-penicillamine (PA) and tetrathiomolybdate (TTM), on polyamine metabolism in DU145 prostate carcinoma, MCF-7 breast carcinoma and JEG-3 choriocarcinoma cells. TETA induced antizyme, down-regulated ODC and inhibited [(14)C] Spd uptake. Moreover, it completely prevented α-difluoromethylornithine (DFMO)-induced increase in [(14)C] Spd uptake, and inhibited [(14)C] putrescine (Put) uptake and ODC activity in vivo Seven-day treatment of DU145 cells with TETA caused growth cessation by reducing intracellular polyamine levels and suppressing the formation of hypusinated eukaryotic translation initiation factor 5A (eIF5A). TETA or its N-acetylated metabolites also inhibited spermine (Spm), diamine and semicarbazide-sensitive amine oxidases and decreased the level of intracellular reactive oxygen species. Moreover, TETA inhibited the utilization of Put as energy source via the tricarboxylic acid (TCA) cycle, as indicated by decreased production of (14)CO2 from [(14)C] Put. These results indicate that TETA attacks multiple proven anticancer drug targets not attributed to copper chelation, which warrants further studies to reveal its potential in cancer chemoprevention and cure.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Mervi T
authors.initials: MT
authors.lastname: Hyvönen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Sebahat
authors.initials: S
authors.lastname: Ucal
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Pasanen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Peräniemi
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Weisell
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St 32, 119991 Moscow, Russia.
authors.forename: Maxim
authors.initials: M
authors.lastname: Khomutov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St 32, 119991 Moscow, Russia.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Khomutov
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland Tuomo.Keinanen@uef.fi.
authors.forename: Tuomo A
authors.initials: TA
authors.lastname: Keinänen
mesh_terms: D006631:Amine Oxidase (Copper-Containing); D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000518:Eflornithine / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008982:Molybdenum / Q000494:pharmacology; D010396:Penicillamine / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D014266:Trientine / Q000494:pharmacology*
chemical_list: D011073:Polyamines; D017382:Reactive Oxygen Species; D013096:Spermine; D008982:Molybdenum; C020809:tetrathiomolybdate; D006631:Amine Oxidase (Copper-Containing); D010396:Penicillamine; D014266:Trientine; D011700:Putrescine; D000518:Eflornithine
keywords: anticancer drug; cancer chemoprevention; copper chelators; ornithine decarboxylase; polyamine metabolism