title: Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer.
abstract: Pancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. Mol Cancer Ther; 15(12); 2875-86. ©2016 AACR.
authors.affiliation: Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic. j.neuzil@griffith.edu.au stepana.boukalova@ibt.cas.cz.
authors.forename: Stepana
authors.initials: S
authors.lastname: Boukalova
authors.affiliation: Institute of Chemical Technology in Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Stursa
authors.affiliation: Institute of Chemical Technology in Prague, Czech Republic.|Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Werner
authors.affiliation: Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Ezrova
authors.affiliation: Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Cerny
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, Australia.
authors.forename: Ayenachew
authors.initials: A
authors.lastname: Bezawork-Geleta
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Pecinova
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, Australia.
authors.forename: Lanfeng
authors.initials: L
authors.lastname: Dong
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Drahota
authors.affiliation: Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic. j.neuzil@griffith.edu.au stepana.boukalova@ibt.cas.cz.|School of Medical Science, Griffith University, Southport, Qld, Australia.
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053078:Membrane Potential, Mitochondrial; D008687:Metformin / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D010101:Oxygen Consumption; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D017382:Reactive Oxygen Species; D008687:Metformin; D042967:Electron Transport Complex I