Epigenetic Reprogramming in Cancer: The Emerging Role of NSAIDs as Therapeutic Modulators

The initiation of cancer is accompanied by a large number of epigenetic changes, underscoring their crucial role in cancer initiation, progression, and metastasis, as well as the development of resistance to therapies (most recently, the formation of drug-resistant oncogenic cell lines). Epigenetic modifications are capable of being reversed, thus making them attractive targets for pharmacological intervention. A large number of agents are available for use that are primarily recognized as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), which primarily provide anti-inflammatory and analgesic benefit. However, this class of agents has also been identified as having the potential to modulate epigenetic mechanisms and consequently exert chemopreventive and anticancer properties. Although the principal mechanism of action of NSAIDs is via the inhibition of the Cyclooxygenase (COX) pathway(s), thus resulting in a decrease in the enzyme activity of prostaglandin synthase, emerging evidence indicates that they also have effects on alternative signaling pathways that are considered COX-independent. This recent evidence indicates that NSAIDs also impact key epigenetic mechanisms such as the regulation of DNA Methyltransferase (DNMT) and Histone Deacetylase (HDAC) enzymes, which are responsible for regulating DNA methylation and histones, respectively, through Peroxisome Proliferator-Activated Receptors (PPARs). The impact of NSAIDs on both DNMT and HDAC enzymes contributes to the reactivation of tumor suppressor genes and the reversal of oncogene activity, inhibition of cell division, and promotion of apoptosis. The efficacy and toxicity of NSAIDs in the treatment of cancer depend on a number of factors, including the type of drug used, dosage, pharmacokinetics, and individual genetic or epigenetic background. This review will examine the emerging roles of NSAIDs as modulating agents for epigenetic mechanisms of action, including the mechanisms of action, pre-clinical and clinical evidence, and potential synergies with existing therapies that are designed to modulate epigenetic mechanisms.