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.
Woynarowska
B
B
Roswell Park Cancer Institute, Grace Cancer Drug Center, Department of Experimental Therapeutics, Buffalo, NY 14263.
Wikiel
H
H
Sharma
M
M
Carpenter
N
N
Fleet
G W
GW
Bernacki
R J
RJ
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000118:Acetylglucosaminidase / Q000032:analysis / Q000037:antagonists & inhibitors*; D002241:Carbohydrates / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010880:Piperidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002241:Carbohydrates; D007527:Isoenzymes; D010880:Piperidines; C053655:2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol; C023735:2-acetamido-2-deoxy-D-glucono-(1,5)-lactone; D017485:1-Deoxynojirimycin; D000118:Acetylglucosaminidase; D000117:Acetylglucosamine