Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low-density lipoprotein receptor-deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft-bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.
- MeSH
- biokatalýza MeSH
- experimentální nádory farmakoterapie metabolismus MeSH
- histondemethylasy antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů chemie farmakologie MeSH
- jaderné proteiny antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- metformin chemie farmakologie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- myši knockoutované MeSH
- myši MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
- MeSH
- antimetabolity antitumorózní chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- cílená molekulární terapie MeSH
- koncentrace vodíkových iontů MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- membránový potenciál mitochondrií MeSH
- metformin chemie farmakologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- modely nemocí na zvířatech MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory slinivky břišní farmakoterapie metabolismus patologie MeSH
- proliferace buněk účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- respirační komplex I antagonisté a inhibitory chemie metabolismus MeSH
- signální transdukce účinky léků MeSH
- spotřeba kyslíku MeSH
- tumor burden účinky léků MeSH
- vazba proteinů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- acidóza laktátová * MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- dyslipidemie * farmakoterapie MeSH
- HDL-cholesterol * účinky léků MeSH
- hnědá tuková tkáň * metabolismus účinky léků MeSH
- hypertriglyceridemie * diagnóza farmakoterapie genetika metabolismus MeSH
- inzulinová rezistence * MeSH
- játra * metabolismus účinky léků MeSH
- laboratorní zvířata * MeSH
- lidé MeSH
- lipoproteiny * terapeutické užití MeSH
- metabolický syndrom * farmakoterapie metabolismus MeSH
- metformin * aplikace a dávkování farmakologie chemie metabolismus terapeutické užití MeSH
- potkani Wistar MeSH
- preklinické hodnocení léčiv * metody statistika a číselné údaje MeSH
- srdce * anatomie a histologie účinky léků MeSH
- triglyceridy * antagonisté a inhibitory farmakologie krev terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
