β-1,3-glucan from Euglena gracilis: a promising epidrug targeting epigenetic regulators PRMTs and SIRTs for therapeutic applications in ovarian cancer.

Abstract

Natural products serve as a valuable resource in drug discovery and the identification of bioactive molecules in the field of epimedicine, which targets epigenetic regulator enzymes through epidrugs. In this study, β-1,3-glucan (BG), a natural storage polysaccharide in Euglena gracilis, a well-known immunostimulatory agent, is propounded as a promising epidrug. To elucidate the therapeutic efficacy of BG against ovarian cancer, the molecular interactions between BG and epigenetic regulators, Protein Arginine Methyltransferases (PRMTs) and Sirtuins (SIRTs) were investigated using computational methods followed by in vitro gene expression studies in SKOV-3 ovarian cancer cell line. The binding energies of PRMT5 and SIRT5 against BG were observed as -65.5 and -68.2 kcal/mol, respectively. The in vitro cytotoxic effects of BG against human ovarian cancer cell line, SKOV-3 showed an IC₅₀ of 150 µg/mL at 48 h. Significant epigenetic modifications were observed to be influenced by BG which increased the gene expression of PRMT5, SIRT5 and Nrf2 to 0.3, 0.5, and 0.7 fold-change respectively, while the Nrf1/2 plasmid showed reduced reporter activity by 29%. Collectively, both in silico and in vitro studies provided valuable insights into the epigenetic regulation of PRMT5 and SIRT5 by BG via Nrf1/2. Nonetheless, further preclinical and clinical investigations are essential to validate the therapeutic properties of BG as an epidrug against ovarian cancer.