Selenium-Based Novel Epigenetic Regulators Offer Effective Chemotherapeutic Alternative with Wider Safety Margins in Experimental Colorectal Cancer

Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Despite the critical involvement of epigenetic modifications in CRC, the studies on the chemotherapeutic efficacy of various epigenetic regulators remain limited. Considering the key roles of histone deacetylases (HDACs) in the regulation of diverse cellular processes, several HDAC inhibitors are implied as effective therapeutic strategies. In this context, suberoylanilide hydroxamic acid (SAHA), a 2^nd-generation HDAC inhibitor, showed limited efficacy in solid tumors. Also, side effects associated with SAHA limit its clinical application. Based on the redox-modulatory and HDAC inhbitiory activities of essential trace element selenium (Se), the anti-carcinogenic potential of Se substituted SAHA, namely, SelSA-1 (25 mg kg⁻¹), was screened for it enhanced anti-tumorigenic role and wider safety profiles in DMH-induced CRC in Balb/c mice. A multipronged approach such as in silico, biochemical, and pharmacokinetics (PK) has been used to screen, characterize, and evaluate these novel compounds in comparison to existing HDAC inhibitor SAHA. This is the first in vivo study indicating the chemotherapeutic potential of Se-based novel epigenetic regulators such as SelSA-1 in any in vivo experimental model of carcinogenesis. Pharmcological and toxicity data indicated better safety margins, bioavailability, tolerance, and elimination rate of SelSA-1 compared to classical HDAC inhibitor SAHA. Further, histological and morphological evidence demonstrated enhanced chemotherapeutic potential of SelSA-1 even at lower pharmacological doses than SAHA. This is the first in vivo study suggesting Se-based novel epigenetic regulators as potential chemotherapeutic alternatives with wider safety margins and enhanced anticancer activities.