Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation

Abstract

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic agents or radiation for targeting DNA-protein complex. The positive results obtained with these combined approaches in preclinical cancer models demonstrate the potential impact DNMT inhibitors may have in treatments of different cancer types. Therefore, as the emerging interest in use of DNMT inhibitors as a potential chemo- or radiation sensitizers is constantly increasing, further clinical investigations are inevitable in order to finalize and confirm the consistency of current observations.The present article will provide a brief review of the biological significance and rationale for the clinical potential of DNMT inhibitors in combination with other chemotherapeutics or ionizing radiation. The molecular basis and mechanisms of action for these combined treatments will be discussed herein.

DNA Methylation and Histone Deacetylation: Interplay and Combined Therapy in Cancer

“…In addition to the observation that HDAC and DNMT inhibitors can reactivate epigenetically silenced tumor suppressor genes and/or inhibit DNA repair, making conventional treatment regimens more effective, another possible mechanism behind this synergy is that the open chromatin structure induced by epigenetic agents makes DNA more accessible for chemotherapy drugs and radiation (Falk et al, 2008)(see Figure 1). These results show clinical potential for using combinations of epigenetic drugs and conventional agents, especially to overcome or prevent chemotherapy resistance (reviewed by (Gravina et al, 2010) and (Thurn et al, 2011)). …”

Epigenetic therapy in gastrointestinal cancer: the right combination

“…The DNMT inhibitor 5-azacitidine (5-AC) incorporates preferentially into RNA while 5-Aza-2'-deoxycytodine (DAC) incorporates mainly into DNA [Derissen et al 2013]. This difference between incorporation into RNA and DNA leads to increased potency with DAC and may result in increased secondary or off-target effects with 5-AC due to integration into the RNA of quiescent, nondividing cells [Gravina et al 2010].…”

Screening for Compounds That Modulate Epigenetic Regulation of the Transcriptome: An Overview

“…More potent and selective DNMT inhibitors potentially with less toxicity are in development, including zebularine. 17,18 Due to their abilities to produce global demethylation, both azacitidine and decitabine have been clinically tested with other FDA-approved chemotherapeutics in clinical cancer trials. Indeed, both agents, at low doses, appear to enhance efficacy of lenalidomide, carboplatin, imatinib, and gemtuzumab for the treatment of several cancer types.…”