Rutinosides-derived from Sarocladium strictum 6-O-α-rhamnosyl-β-glucosidase show enhanced anti-tumoral activity in pancreatic cancer cells

Abstract

Background Low targeting efcacy and high toxicity continue to be challenges in Oncology. A promising strat‑ egy is the glycosylation of chemotherapeutic agents to improve their pharmacodynamics and anti-tumoral activity. Herein, we provide evidence of a novel approach using diglycosidases from fungi of the Hypocreales order to obtain novel rutinose-conjugates therapeutic agents with enhanced anti-tumoral capacity. Results Screening for diglycosidase activity in twenty-eight strains of the genetically related genera Acremonium and Sarocladium identifed 6-O-α-rhamnosyl-β-glucosidase (αRβG) of Sarocladium strictum DMic 093557 as candidate enzyme for our studies. Biochemically characterization shows that αRβG has the ability to transglycosylate bulky OH-acceptors, including bioactive compounds. Interestingly, rutinoside-derivatives of phloroglucinol (PR) resor‑ cinol (RR) and 4-methylumbelliferone (4MUR) displayed higher growth inhibitory activity on pancreatic cancer cells than the respective aglycones without signifcant afecting normal pancreatic epithelial cells. PR exhibited the highest efcacy with an IC50 of 0.89 mM, followed by RR with an IC50 of 1.67 mM, and 4MUR with an IC50 of 2.4 mM, whereas the respective aglycones displayed higher IC50 values: 4.69 mM for phloroglucinol, 5.90 mM for resorcinol, and 4.8 mM for 4-methylumbelliferone. Further, glycoconjugates signifcantly sensitized pancreatic cancer cells to the standard of care chemotherapy agent gemcitabine. Conclusions αRβG from S. strictum transglycosylate-based approach to synthesize rutinosides represents a suit‑ able option to enhance the anti-proliferative efect of bioactive compounds. This fnding opens up new possibilities for developing more efective therapies for pancreatic cancer and other solid malignancies.