Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

Abstract

Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.

HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through theEWSR1promoter in Ewing sarcoma

“…However, this carries a high toxicity due to their effects on nonspecific targets (Hontecillas-Prieto et al, 2020). Therefore, we hypothesized that it would be more appropriate to develop and evaluate the effects of selective HDAC inhibitors, which could maintain the effectiveness on EWSR1-FLI1 depletion while at the same time reducing treatment toxicity (de Nigris et al, 2020;Hontecillas-Prieto et al, 2020;Sun et al, 2018;Tang et al, 2017). We thus performed a screen of 43 epigenetic drugs, most of them known to modulate HDAC activity.…”

“…However, it remains to be determined which HDAC(s) are involved specifically in the regulation of EWSR1-FLI1 expression. Usually, the treatment with non-selective HDAC inhibitors in patients is an imprecise mechanism associated with increased toxicity (Hontecillas-Prieto et al, 2020). Hence, the identification of specific HDAC(s) involved in the regulation of EWSR1-FLI1, and the use of selective inhibitors, may improve efficacy and avoid toxicity of treatments, and enhance our understanding about the regulatory mechanisms of EWSR1-FLI1.…”

Novel Approaches to Epigenetic Therapies: From Drug Combinations to Epigenetic Editing

“…The processes of acetylation and deacetylation are catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively [ 33 ]. HATs transfer an acetyl group from acetyl CoA to form ε-N-acetyl-lysine, whereas HDACs remove acetyl groups from histone tails [ 38 ]. Importantly, histone acetylation is associated with relaxed chromatin structure, making target genes more accessible for transcription factors and leading to their unconstrained expression.…”

“…The mechanisms by which HDACs contribute to cancer are diverse. It has been shown in numerous studies that overexpression of HDACs results in tumor cell proliferation, angiogenesis, metastasis, resistance to apoptosis, and alteration of the cell cycle [ 38 ]. These actions are a result of oncogenic pathways activation due to the diminished expression of tumor suppressor genes and/or activation of oncogenes [ 39 ].…”

“…Furthermore, HDACi, based on their mechanism of action, can be divided into two groups—one acting on all HDAC classes (however not including sirtuins), called pan-HDAC inhibitors (pan-HDACi), and the other, acting on and targeting a specific class of HDACs (selective HDACi) [ 41 ]. HDACi can also be grouped into five classes based on their chemical structure: hydroxamates, cyclic peptides, short chain fatty (aliphatic) acids, benzamides, and sirtuin inhibitors [ 38 ]. The major mechanisms of action of HDACi involve the cell cycle arrest by p53-dependent or -independent induction of the cyclin-dependent kinase inhibitor p21CIP/WAF1; downregulation of oncogenes, e.g., c-MYC and c-SRC; enhanced ROS formation; and autophagy induction [ 42 ].…”