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

In the last decade, epigenetic drugs (such as inhibitors of DNA methyltransferases and histone deacetylases) have been intensively used for cancer treatment. Their applications have shown high anticancer effectivity and tolerable side effects. However, they are unfortunately not effective in the treatment of some types and phenotypes of cancers. Nevertheless, several studies have demonstrated that problems of drug efficacy can be overcome through the combined application of therapeutic modulates. Therefore, combined applications of epigenetic agents with chemotherapy, radiation therapy, immunotherapy, oncolytic virotherapy and hyperthermia have been presented. This review summarizes and discusses the general principles of this approach, as introduced and supported by numerous examples. In addition, predictions of the future potential applications of this methodology are included.

• MeSH
• DNA modifikační methylasy farmakologie   MeSH
• epigeneze genetická účinky léků   MeSH
• histonacetyltransferasy antagonisté a inhibitory   MeSH
• histondemethylasy antagonisté a inhibitory   MeSH
• histonmethyltransferasy antagonisté a inhibitory   MeSH
• inhibitory histondeacetylas farmakologie   terapeutické užití   MeSH
• kombinovaná terapie metody   MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nádory farmakoterapie   genetika   terapie   MeSH
• objevování léků metody   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH