Inhibition of fibroblast hyaluronic acid production by suramin.
Hyaluronic acid (HA) is an extracellular matrix glycosaminoglycan localized in the stroma of solid tumors, where it facilitates cell movement and thus tumor invasion and metastasis. This localization of HA is due to its synthesis by stromal fibroblasts in response to paracrine factors produced by the tumor. Such tumor-stromal interactions have been shown to be crucial to the development and progression of prostate cancer. Suramin is an effective antitumor agent in hormone-refractory prostate cancer, but its mechanism(s) of action is not well understood. However, the properties of suramin as an agent which disrupts growth factor action, and the importance of tumor-stroma interactions in prostate tumor development and in HA synthesis led us to study the effect of suramin on HA synthesis. Suramin inhibited HA synthesis by calf serum-stimulated Swiss 3T3 fibroblasts at clinically relevant concentrations (IC50 = 183 micrograms/mL). Increasing the serum concentration from 10 to 20% did not change the IC50 for HA synthesis, but increased the IC50 for [3H]thymidine incorporation from 206 to 342 micrograms/mL, indicating that the antiproliferative effect of suramin can be dissociated from its effect on HA synthesis. Suramin did not alter the cellular concentrations of the two precursors for HA synthesis (UDP-glucuronic acid and UDP-N-acetylglucosamine) at early time points and did not inhibit the HA synthetase activity of isolated membranes at concentrations up to 800 micrograms/mL.(ABSTRACT TRUNCATED AT 250 WORDS)
August
E M
EM
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Duncan
K L
KL
Malinowski
N M
NM
Cysyk
R L
RL
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division; D003470:Culture Media; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D016695:Glycosyltransferases; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology; D013498:Suramin / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014166:Transferases; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism; D029867:Xenopus Proteins
D003470:Culture Media; D008565:Membrane Proteins; D029867:Xenopus Proteins; D014535:Uridine Diphosphate Glucuronic Acid; D014537:Uridine Diphosphate N-Acetylglucosamine; D013498:Suramin; D006820:Hyaluronic Acid; D004247:DNA; D014166:Transferases; D016695:Glycosyltransferases; D014453:Glucuronosyltransferase; C056944:HAS1 protein, Xenopus; D000076002:Hyaluronan Synthases; D013936:Thymidine