Inhibition of human ovarian carcinoma cell- and hexosaminidase- mediated degradation of extracellular matrix by sugar analogs.

Human ovarian carcinoma (HOC) cell beta-N-acetylglucosaminidase (beta-NAG, EC 3.2.1.30) was found to be present in three isoenzymatic forms. All three forms were capable of degrading ECM. Therefore, inhibitors of beta-NAG were sought as potential anti-invasive agents. Two sugar analogs, 2-acetamido-2-deoxy-1,5-gluconolactone (CD80110) and 2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol (CD 86022), were evaluated for their ability to inhibit 1) human ovarian carcinoma beta-NAG isoenzyme activities, 2) degradation of radiolabeled ECM mediated by HOC cells and beta-NAG, and 3) cell growth. Both compounds were found to be competitive inhibitors of beta-NAG isoenzyme activities, with Ki values similar for all isoenzymes (2-8 microM). CD 80110 and CD 86022 inhibited HOC cell-mediated degradation of [3H]glucosamine labeled ECM without notable effect on cell growth. Enzyme-mediated degradation of ECM was also inhibited by both sugar analogs. Analysis of degradation products after cell- or enzyme-mediated digestion of ECM revealed a decrease in the amount of both free aminosugars and high molecular material caused by inhibitors. These results support a role for beta-NAG in degradation of extracellular matrix components and suggest the usefulness of hexosaminidase inhibitors as potential antiinvasive agents.