Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer

Abstract

The development of resistance to anti-cancer therapeutics remains one of the core issues preventing the improvement of survival rates in cancer. Therapy resistance can arise in a multitude of ways, including the accumulation of epigenetic alterations in cancer cells. By remodeling DNA methylation patterns or modifying histone proteins during oncogenesis, cancer cells reorient their epigenomic landscapes in order to aggressively resist anti-cancer therapy. To combat these chemoresistant effects, epigenetic modifiers such as DNA hypomethylating agents, histone deacetylase inhibitors, histone demethylase inhibitors, along with others have been used. While these modifiers have achieved moderate success when used either alone or in combination with one another, the most positive outcomes were achieved when they were used in conjunction with conventional anti-cancer therapies. Epigenome modifying drugs have succeeded in sensitizing cancer cells to anti-cancer therapy via a variety of mechanisms: disrupting pro-survival/anti-apoptotic signaling, restoring cell cycle control and preventing DNA damage repair, suppressing immune system evasion, regulating altered metabolism, disengaging pro-survival microenvironmental interactions and increasing protein expression for targeted therapies. In this review, we explore different mechanisms by which epigenetic modifiers induce sensitivity to anti-cancer therapies and encourage the further identification of the specific genes involved with sensitization to facilitate development of clinical trials.

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

“…Moreover, the cancer cells with a unique portfolio of epigenetic changes are different from their normal counterparts. Accumulation of these altered epigenetic changes allows cancer cells to solidify their exclusive phenotype through dysregulated gene expression changes [75][76][77]. Furthermore, the accumulation of altered epigenetic changes can also promote resistance to therapy through the acquisition of pro-survival signaling [75,78].…”

“…Accumulation of these altered epigenetic changes allows cancer cells to solidify their exclusive phenotype through dysregulated gene expression changes [75][76][77]. Furthermore, the accumulation of altered epigenetic changes can also promote resistance to therapy through the acquisition of pro-survival signaling [75,78]. The epigenetic histone acetylation alterations induced by aberrant expression of HDACs can be reversed by pharmacological inhibition of HDACs with HDACIs.…”

“…They stimulate cell cycle arrest by upregulating p21Cip1 and downregulating cyclins [69,84,85]. They also do the following: 1) Induce intrinsic and extrinsic apoptosis pathways causing apoptosis [75,86,87]. 2) Induce autophagy [88].…”

“…4) Alter expression of nonhistone proteins including transcription factors and regulators, inflammation/immune response mediators, chaperones, DNA repair enzymes, and structural proteins [69,82,83,90]. These features of HDACIs are exploited as promising anticancer epi-drugs and several HDACIs have entered clinical trials in both hematologic and solid tumors [70,[72][73][74][75][81][82][83]90]. As such, HDACIs are investigated mainly as anticancer epi-drugs, even though HDAC enzymes also play a crucial role in other diseases such as cardiovascular disease [91], neurological disorders [92], immunological processes and viral infections [93], and other disorders [94].…”

“…One of the main reasons for ineffectiveness is, cancer cells can evade drug-induced effects by eliciting other compensatory survival pathways due to the emergence of pharmacological resistance. Interestingly, HDACIs also exhibit anticancer effect by disrupting pro-survival signaling through epigenetic drug-induced sensitization mechanisms [75].…”