The pharmacoepigenetic paradigm in cancer treatment

Abstract

Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.

Keywords: DNA methyltransferase inhibitors; clinical trials; epigenetic drugs; histone acetyltransferase inhibitors; histone deacetylase inhibitors; histone methyltransferase inhibitors.

FIGURE 1

The epigenetic machinery plays an essential role in shaping the conformation of chromatin and regulating genome functionality. DNA is intricately packed and wound around a core composed of histone octamers, thus forming nucleosomes, the fundamental structural units of chromatin. This sophisticated network of epigenetic modifications, encompassing DNA methylation and histone modifications, profoundly impacts the structure of chromatin and the functionality of the genome. Central to epigenetics are enzymes that serve three primary roles: adding (writers), recognizing (readers), and removing (erasers) epigenetic marks on DNA or histone tails. DNA methylation, primarily carried out by DNA methyltransferases (DNMTs), can be reversed by ten-eleven translocation enzymes (TETs) or can diminish progressively over successive cell divisions. Among histone modifications, acetylation and methylation have been extensively studied. The equilibrium of histone methylation is controlled by the opposing activities of histone methyltransferases (HMTs) and histone demethylases (HDMs). In a similar vein, histone acetylation levels are modulated by the concerted efforts of histone acetyltransferases (HATs) and histone deacetylases (HDACs), which add or remove acetyl groups from lysine residues on the histone tails, respectively. This “epigenetic code” is interpreted by specific reader or effector proteins that selectively bind to certain types of modifications. For instance, methyl-CpG-binding domain (MBDs) proteins bind to methylated DNA, whereas bromodomain and extraterminal domain proteins (BETs) recognize acetylated lysines. These epigenetic modifications play a critical role in altering chromatin conformation, leading to either the transcriptional silencing or activation of genes, often through the recruitment of additional proteins to these sites.