Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors

Abstract

Introduction Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues. Areas covered This review highlights the evidence available till date on the influence of different epigenetic modifications on the response to Top I inhibitors as well as the implications of targeting epigenetic alterations for improving the efficacy and safety of Top I inhibitors. Expert opinion The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention. HIGHLIGHTS Epigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors. Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them. Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms. The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors. MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors. lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors. Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

“…The addition of acetyl groups, referred to as histone acetylation, serves to activate the corresponding chromosomal region, while their removal (deacetylation) leads to deactivation. Key enzymes in the regulation of gene expression are histone deacetylases (HDACs) [12,239].…”

“…Modification leading to hypomethylation can either increase or decrease the sensitivity of cells to topoisomerase inhibitors due to altered mechanisms. Also, it has been reported that the dysregulation of histone acetyltransferase (HAT) and histone deacetylases (HDACC), which play a key role in regulating the level of acetylation in histone proteins, results in resistance against topoisomerase inhibitors (Figure 4) [12,[248][249][250][251][252][253][254][255][256][257][258][259][260].…”

“…The interfering role of microRNAs and long noncoding RNAs (lncRNAs) is suggested to modulate the levels of TOPI and TOPII enzymes that, in turn, are related to topoactive drug resistance in cancer cells [12,[283][284][285][286]. The regulatory role of microRNAs and lncRNAs is extensively reported and is associated with oncogenic as well as tumor suppressor roles in cancer cells.…”

“…Camptothecin (CPT), an alkaloid, discovered in 1958, is an inhibitor of TOPI. FDA-approved derivatives like topotecan and irinotecan target TOPI, while TOPII inhibitors like the anthracycline-based drug doxorubicin (DOX) cause cytotoxic DNA double-strand breaks [10][11][12]. Although these topo-active drugs are extremely effective and utilized to treat a wide variety of cancers, they face the common hurdle of resistance development in tumor cells, necessitating novel approaches.…”

Genetic and epigenetic alterations in human cancers

“…Disruptions in epigenetic processes can lead to altered gene functions and cause cellular neoplastic transformation. The epigenetic modifications precede genetic changes and usually occur at the early stage of tumor development [119,120]. Among the epigenetic disorders in carcinogenesis, the most studied processes are the abovementioned ones, namely, gene promoter methylation, histone acetylation and methylation, changes in chromatin state, and expression of non-coding RNAs.…”