Epigenetic drugs as pleiotropic agents in cancer treatment: Biomolecular aspects and clinical applications

Abstract

In the last three decades huge efforts have been made to characterize genetic defects responsible for cancer development and progression, leading to the comprehensive identification of distinct cellular pathways affected by the alteration of specific genes. Despite the undoubtable role of genetic mechanisms in triggering neoplastic cell transformation, epigenetic modifications (i.e., heritable changes of gene expression that do not derive from alterations of the nucleotide sequence of DNA) are rapidly emerging as frequent alterations that often occur in the early phases of tumorigenesis and that play an important role in tumor development and progression. Epigenetic alterations, such as modifications in DNA methylation patterns and post-translational modifications of histone tails, behave extremely different from genetic modifications, being readily revertable by ''epigenetic drugs'' such as inhibitors of DNA methyl transferases and inhibitors of histone deacetylases. Since epigenetic alterations in cancer cells affect virtually all cellular pathways that have been associated to tumorigenesis, it is not surprising that epigenetic drugs display pleiotropic activities, being able to concomitantly restore the defective expression of genes involved in cell cycle control, apoptosis, cell signaling, tumor cell invasion and metastasis, angiogenesis and immune recognition. Prompted by this emerging clinical relevance of epigenetic drugs, this review will focus on the large amount of available data, deriving both from in vitro experimentations and in vivo pre-clinical and clinical studies, which clearly indicate epigenetic drugs as effective modifiers of cancer phenotype and as positive regulators of tumor cell biology with a relevant therapeutic potential in cancer patients.

Genetic and epigenetic alterations in breast cancer: What are the perspectives for clinical practice?

“…Epigenetic modifications affect the arrangement in gene expression by two main mechanisms: methylation of CpG rich islands present in the genomic DNA (Romano, Micheli, Pacilio & Giordano, 2000;Sigalotti et al, 2007) and methylation and/or acetylation of histones H3 and H4 (Jones & Baylin, 2002;Sparmann & van Lohuizen, 2006). Both events do not affect the DNA sequence at all and, yet, they have important implications on the regulation of transcriptional activity.…”

“…So far, four types of DNA methyltransferases (DNMT) that mediate the methylation of CpG islands have been identified: DNMT1, DNMT2, DNMT3a and DNMT3b (Sigalotti et al, 2007).…”

“…Studies on epigenetic modifications eventually led to the formulation of so-called epigenetic drugs for the treatment of cancer (Sigalotti et al, 2007;Xu, Parmigiani & Marks, 2007). Epigenetic drugs essentially fall in two categories: inhibitors of DNMT to remove aberrant patterns of DNA methylation (Sigalotti et al, 2007) and inhibitors of HDACs, which are termed HDACi (Xu, Parmigiani & Marks, 2007).…”

“…Epigenetic drugs essentially fall in two categories: inhibitors of DNMT to remove aberrant patterns of DNA methylation (Sigalotti et al, 2007) and inhibitors of HDACs, which are termed HDACi (Xu, Parmigiani & Marks, 2007).…”

“…Chemically speaking, HDACi are based on aliphatic acids, hydroxamic acids, benzamides and cyclic tetrapeptides (Table 1) (Sigalotti et al, 2007;Xu, Parmigiani & Marks, 2007). The HDACi listed I Table 1 have been used either in phase I or phase II clinical trials, with the only exception of SAHA.…”