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  • Pharmacological Targeting of the Cancer Epigenome: Recent Trends and Challenges

  • Mahsa Merikhi Khosroshahi,1,* Asiyeh Jebelli,2
    1. Kharazmi University
    2. Department of Cell and Molecular Biology, Faculty of Biological Sciences,Kharazmi University


  • Introduction: Epigenetics refers to the study of reversible heritable changes in gene expression without alterations in the DNA sequence. The main epigenetic mechanisms include histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA. The epigenetic upregulation of oncogenes and downregulation of tumor suppressor genes are key processes in the development of cancer. Therefore, epigenetic alterations are becoming a therapeutic target. This study highlights the evolving role of epigenetic drugs (epi-drugs) in cancer therapy.
  • Methods: FDA has approved the epi-drugs: DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and histone methyltransferase inhibitors (HMTi) for the treatment of several cancers. Besides, drug repurposing refers to the process of discovering a new medical indication for a drug that was approved for another indication. Some epi-drugs that were designed for specific purposes have been repurposed for cancer therapy.
  • Results: The bromodomain and extra-terminal motif (BET) protein that recognizes acetylated lysine is a promising target in cancer therapy. BET inhibitor (BETi) epi-drugs have anti-cancer activity in both pre-clinical and clinical trials and function by binding reversibly to the bromodomain of BET proteins and subsequently disrupting vital histone-protein interactions. As DNA methylation and histone post-translational modifications operate in parallel, there is an ongoing interest in combining epigenetic therapies, as this may lead to an increase in the efficacy of each treatment. The re-expression of methylated genes silenced in cancer occurs after the combination of a DNMTi followed by HDACi, leading to a substantial interest in the combination of epi-drugs. There are several ongoing and completed clinical trials of combinations of DNMTi, HDACi, and HMTi for the treatment of cancer. A phase II multicenter study of oral azacitidine in combination with romidepsin in patients with peripheral T-cell lymphoma demonstrated the combination treatment induced a high response rate and increased the remission of these patients. Furthermore, the combination the HDACi, belinostat, with the HMTi, tazemetostat, promoted antigen presentation pathways in germinal center diffuse large B-cell lymphoma cells. The combination therapy could restore immunogenicity in these cells. There are also some repurposed epi-drugs. The FDA has approved two repurposed epigenetic modulators for cancer therapy: 5-azacytidine and 5-aza-20-deoxycytidine. They were incorporated into DNA and inhibited DNA methylation. Apicidin, a fungal metabolite, has been repurposed as an inhibitor of HDACs. Apicidin reduces HDAC3 and HDAC4 expression and activity, leading to increased histone H3 and H4 acetylation in endometrial and ovarian cancer cell lines. In an in vivo mouse model, this repurposed drug inhibits tumor growth and decreases HDAC8 expression. Carbamazepine is an FDA-approved drug for the control of psychomotor or focal seizures, and, in recent years, it has been investigated as an HDACi. In breast cancer cell lines, carbamazepine inhibits HDAC6 activity, increases Hsp90 acetylation, and upregulates p21 gene expression. Clorgyline and pargyline have been repurposed as LSD1 inhibitors for solid and liquid tumors with decreasing histone H3 methylation, thus promoting an open chromatin state in cancers. Ribavirin was approved by the FDA for the treatment of viral infections. However, in recent years, ribavirin has been introduced as an HMTi. Ribavirin prevents histone H3 trimethylation in numerous solid tumors. Berberine, a natural compound used for the treatment of parasitic and fungal infections, has been repurposed as a DNMT and HDAC dual inhibitor. Regarding DNMT inhibition, in a multiple myeloma cell line, berberine downregulated DNMTs gene expression and activity, restoring p53 expression through DNA hypomethylation.
  • Conclusion: A considerable expansion in the understanding of epigenetics application in cancer therapy has been witnessed. Most studies used a small range of drug concentrations in a limited number of cell lines, and mainly in 2D settings, thus failing to demonstrate efficacy in more complex models such as 3D culture and in vivo assays. More appropriate and complex cellular models are required to better represent human physiology and disease, such as 3D cell models. Another main drawback of epi-drugs is their less promising results in solid tumours, compared with their success in treating hematological malignancies. The use of novel delivery methods of epi-drugs may address this issue, enabling a more effective intra-tumor delivery of these drugs. Furthermore, the use of multi-target epi-drugs in the future may provide advantages over single- target cancer therapies by treating difficult-to-treat, heterogeneous, and drug-resistant tumors.
  • Keywords: epigenetic drugs, cancer therapy, drug repurposing

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