Natural substances as inhibitors of the tumor target human hyaluronidase Hyal-1

Lengers I, Orlando Z, Melzig MF, Buschauer A, Hensel A, Jose J

Abstract

The negatively charged polysaccharide hyaluronic acid (HA) assembled from repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. Its chain size triggers different physiological andpathophysiological functions. Space filling, anti-inflammatory and antiangiogenic effects are caused by high molecular weight HA (>20 kDa). HA hydrolization by hyaluronidases leads to low molecular weight HA (<20kDa), resulting in inflammatory and angiogenic effects [1]. The degradation of HA is mainly catalyzed by human hyaluronidase Hyal-1. It has been demonstrated that in prostate or bladder tumour cells the expressionlevel of Hyal-1 was elevated [2,3]. For this reason Hyal-1 is an interesting target for drug discovery. The surface display of active Hyal-1 on Escherichia coli, via Autodisplay, enables the screening for potential inhibitorsin a whole cell system. Based on this technique we determined the inhibitory effect of different plant extracts and triterpenoid saponins on human Hyal-1. The IC50 values of the extracts of Malvae sylvestris flos,Equiseti herba and Ononidis radix were determined to lay between 1.4 and 1.7 mg/mL. The obtained IC50 values for the triterpenoid saponins, glycyrrhizic acid (reference inhibitor), gypsophila saponin 2, SA1641 andSA1657 were 177 μM, 108 μM, 296 μM and 371 μM, respectively [4]. These natural substances identified can be used as a starting point for the synthesis of new small molecule inhibitors targeting human Hyal-1.