Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment?

Abstract

Epigenetic alterations, as a cancer hallmark, are associated with cancer initiation, progression and aggressiveness. Considering, however, that these alterations are reversible, drugs that target epigenetic machinery may have an inhibitory effect upon cancer treatment. The traditional drug discovery pathway is time-consuming and expensive, and thus, new and more effective strategies are required. Drug Repurposing (DR) comprises the discovery of a new medical indication for a drug that is approved for another indication, which has been recalled, that was not accepted or failed to prove efficacy. DR presents several advantages, mainly reduced resources, absence of the initial target discovery process and the reduced time necessary for the drug to be commercially available. There are numerous old drugs that are under study as repurposed epigenetic inhibitors which have demonstrated promising results in in vitro tumor models. Herein, we summarize the DR process and explore several repurposed drugs with different epigenetic targets that constitute promising candidates for cancer treatment, highlighting their mechanisms of action.

Efficacy of HDAC Inhibitors Belinostat and Panobinostat against Cisplatin-Sensitive and Cisplatin-Resistant Testicular Germ Cell Tumors

“…HDACs are involved in deacetylation of histone (and non-histone) proteins, usually associated with transcription repression, and are grouped into four classes. Changes in the expression of these enzymes have been reported in several cancers and, importantly, inhibitors have been used effectively as cancer treatment [ 40 ], including repurposed drugs (e.g., antifungal trichostatin A (TSA)) or drugs used for treating epilepsy (e.g., valproic acid or carbamazepine) [ 41 ], as well as the more recently developed inhibitors, some already approved by the FDA and others on clinical trial [ 42 ]. Overall, only a few studies assessed HDACs expression in detail.…”

Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy

“…For instance, gene promoters which are mainly embedded in CpG islands (70%) are normally unmethylated, thus allowing transcription. Aberrant hypermethylation patterns of these gene regulatory elements lead to transcriptional inactivation and are tumor-type specific as well as a common hallmark of cancer (9). Alternatively, during diseases, other alterations occur, like the demethylation of the gene body.…”

“…For a few years, the design of therapeutic strategies has been a growing field of query for single-target epigenetic drugs (epidrugs); however, the traditional epidrug discovery pathway is time-consuming and expensive (8,9). Hence, a promising strategy for epidrug development is based on tracing novel potential epi-targets in previously approved drugs through a process called drug repositioning or repurposing (10,11).…”

“…Hence, a promising strategy for epidrug development is based on tracing novel potential epi-targets in previously approved drugs through a process called drug repositioning or repurposing (10,11). Epidrug repurposing allows exploring a wide diversity of molecular combinations in multifactorial diseases such as cancer, where combinational epigenetic therapies are likely to be more effective than monotherapy to overcome chemotherapy resistance (9). This review focuses on the emerging area of epidrug repurposing, highlighting strategies to enhance cancer therapy.…”

“…Current HAT HMT, HDM, and BET inhibitors repurposed with epigenetic applications in cancer therapy [*modified from Moreira-Silva et al,(9)]. …”