Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
27765848
DOI
10.1158/1535-7163.mct-15-1021
PII: 1535-7163.MCT-15-1021
Knihovny.cz E-resources
- MeSH
- Apoptosis drug effects MeSH
- Molecular Targeted Therapy MeSH
- Hydrogen-Ion Concentration MeSH
- Rats MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial MeSH
- Metformin chemistry pharmacology MeSH
- Mitochondria drug effects metabolism MeSH
- Disease Models, Animal MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Pancreatic Neoplasms drug therapy metabolism pathology MeSH
- Cell Proliferation drug effects MeSH
- Antimetabolites, Antineoplastic chemistry pharmacology MeSH
- Reactive Oxygen Species metabolism MeSH
- Electron Transport Complex I antagonists & inhibitors chemistry metabolism MeSH
- Signal Transduction drug effects MeSH
- Oxygen Consumption MeSH
- Tumor Burden drug effects MeSH
- Protein Binding MeSH
- Dose-Response Relationship, Drug MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Metformin MeSH
- Antimetabolites, Antineoplastic MeSH
- Reactive Oxygen Species MeSH
- Electron Transport Complex I MeSH
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.
Biomedical Research Centre University Hospital Hradec Kralove Czech Republic
Institute of Biotechnology Czech Academy of Sciences Vestec Czech Republic
Institute of Chemical Technology Prague Czech Republic
Institute of Physiology Czech Academy of Sciences Prague Czech Republic
School of Medical Science Griffith University Southport Qld Australia
References provided by Crossref.org
Effects of metabolic cancer therapy on tumor microenvironment
Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy
Cytochrome c Oxidase Subunit 4 Isoform Exchange Results in Modulation of Oxygen Affinity
Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2
Metformin directly targets the H3K27me3 demethylase KDM6A/UTX
Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism
Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production
