Contrary to differentiated cells, cancer cells predominantly convert glucose to lactate even under conditions of adequate oxygen supply (“Warburg effect”). The initial enzyme implicated in this route is hexokinase, which transforms D-glucose into D-glucose-6-phosphate. We proposed the use of different polyphenols (resveratrol, epigallocatechin gallate, pterostilbene, phloretin) and their derivatives (α-glucosides and acylated α-glucosides) to inhibit this enzyme. For this study, we used
Saccharomyces cerevisiae hexokinase, whose two isoforms show high resemblance at the active site with human hexokinase HK2. Remarkably, most of the assayed compounds inhibited the enzyme more than 50 % in the standard assay. Among them, phloretin 4’-O-(6’’-O-octanoyl)-α-D-glucopyranoside showed the highest inhibition and was studied in depth to determine the inhibition pattern and inhibition constant. Computational models of inhibition were carried out with the three molecules displaying the highest inhibition, and correlated adequately with the observed inhibitory effects on the enzyme. The inhibitory effect of several of the assayed polyphenols on hexokinase and their lack of toxicity renders them promising candidates as adjuvant drugs for cancer therapy.
Ref.: “Inhibition of Yeast Hexokinase by Acyl Glucosides of Phloretin and its Implication in the Warburg Effect”. Fadia V. Cervantes, Lucía Fernandez-Arrojo, Cristina Coscolin, Alicia Berrojo, José L. Gonzalez-Alfonso, José M. Perez de la Lastra, Manuel Ferrer, Celia M. Curieses-Andres, Celia Andres-Juan, Antonio O. Ballesteros, Eduardo Perez-Lebeña, and Francisco J. Plou. Chemistry Select (2024) https://doi.org/10.1002/slct.202401086
