T140: Epigenetically active xenobiotics in cancer prevention and therapy optimization

Abstract

Nowadays the term “epigenetics” is described as regulation of gene expression persisting from one cell division to the next, despite a lack of changes in the underlying DNA sequence. The “epigenome” refers to different epigenetic states of a cell recognized as heritable environment influence on genome. The main epigenetic phenomena in mammals are DNA methylation and histone modifications, which are tightly interdependent. Many authors classify microRNA regulation as a third epigenetic phenomenon. Moreover, recently the discussion has been open that many different factors modifying DNA conformation represent a new class of epigenetic agents. In response to various environmental stimuli, cells produce different epigenetic changes that determine either an active or a repressed chromatin state. Epigenetic perturbations have been shown to associate with exposure to a range of drugs and toxicants, including non-genotoxic carcinogens. Consequently, on one hand, potential impact of epigenomics on drug development is under consideration as even well-known pharmacological drugs were shown to cause epigenetic changes that may be beneficial or hazardous. In particular, epigenetic effects were described for synthetic estrogens and contraceptives, beta-blockers and fluoroquinolone antibiotics, neuroleptics and anesthetics, chemotherapeutics and statins. Drug influence on gene silencing might have some therapeutic advantage in addition to the unfavourable effects. In particular, valproate, hydralazine and procainamide might be utilized to induce gene expression in cancers, where activation of a methylated gene might be of benefit. Screening of xenobiotics for epigenetic activity might identify new potential drugs for some specific diseases. On the other hand, epigenetic aspects of drug safety are investigated intensively. Many recent reviews in this field of research were devoted to the test elaboration for revealing different short-term and longer-lasting epigenetic changes modifying gene expression. Most of the short-term epigenetic screening tests are based on revealing of xenobiotics to influence on specific enzymes participating in epigenetic modifications, especially DNA methylation and histone modifications. Recently a new model system for the screening of compounds reactivating epigenetically repressed genes was described. It represents HeLa cell population that harbors silent GFP-reporter gene which could be activated via different epigenetic mechanisms. Epigenetic studies of xenobiotic-induced mechanisms will reveal valuable information clarifying both mechanisms of desirable therapy and side effects and open potential drug design directions. The major challenge that remains is to determine how epigenetic control is regulated and how it might be possible to intervene in such processes.