title: Effects on Energy Metabolism of Two Guanidine Molecules, (Boc)2-Creatine and Metformin.
abstract: Several enzymes are involved in the energy production, becoming a possible target for new anti-cancer drugs. In this paper, we used biochemical and in silico studies to evaluate the effects of two guanidine molecules, (Boc)2-creatine and metformin, on creatine kinase, an enzyme involved in the regulation of intracellular energy levels. Our results show that both drugs inhibit creatine kinase activity; however, (Boc)2-creatine displays a competitive inhibition, while metformin acts with a non-competitive mechanism. Moreover, (Boc)2-creatine is able to inhibit the activity of hexokinase with a non-competitive mechanism. Considering that creatine kinase and hexokinase are involved in energy metabolism, we evaluated the effects of (Boc)2-creatine and metformin on the ATP/AMP ratio and on cellular proliferation in healthy fibroblasts, human breast cancer cells (MDA-MB-468), a human neuroblastoma cell line (SH-SY5Y), a human Hodgkin lymphoma cell line (KMH2). We found that healthy fibroblasts were only partially affected by (Boc)2-creatine, while both ATP/AMP ratio and viability of the three cancer cell lines were significantly decreased. By inhibiting both creatine kinase and hexokinase, (Boc)2-creatine appears as a promising new agent in anticancer treatment. Further research is needed to understand what types of cancer cells are most suitable to treatment by this new compound. J. Cell. Biochem. 118: 2700-2711, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences, University of Genova, Largo Paolo Daneo 3, Genova 16132, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Garbati
authors.affiliation: Department of Pharmacy, Biochemistry Laboratory, University of Genova, Viale Benedetto XV 3, Genova 16132, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.affiliation: Department of Earth, Environment and Life Sciences (DISTAV) University of Genova, Corso Europa 26, Genova 16132, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Scarfì
authors.affiliation: Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, Genova 16132, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Salis
authors.affiliation: IRCCS AOU San Martino-IST National Institute for Cancer Research, Biopolymers and Proteomics, Largo Benzi 10, Genova 16132, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.affiliation: IRCCS AOU San Martino-IST National Institute for Cancer Research, Molecular Oncology and Angiogenesis, Largo Benzi 10, Genova 16132, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, Genova 16132, Italy.|Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, Genova 16132, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Damonte
authors.affiliation: Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, Genova 16132, Italy.|Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, Genova 16132, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Millo
authors.affiliation: Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences, University of Genova, Largo Paolo Daneo 3, Genova 16132, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Balestrino
mesh_terms: D045744:Cell Line, Tumor; D003401:Creatine / Q000737:chemistry / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008687:Metformin / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological
chemical_list: D008687:Metformin; D006593:Hexokinase; D003402:Creatine Kinase; D003401:Creatine
keywords: CANCER METABOLISM; CREATINE KINASE; HEXOKINASE