INHIBITION OF FIBROBLAST HYALURONIC-ACID PRODUCTION BY SURAMIN

Hyaluronic acid (HA) is an extracellular matrix glycosaminoglycan loca lized in the stroma of solid tumors, where it facilitates cell movemen t and thus tumor invasion and metastasis. This localization of HA is d ue to its synthesis by stromal fibroblasts in response to paracrine fa ctors produced by the tumor. Such tumor-stromal interactions have been shown to be crucial to the development and progression of prostate ca ncer. Suramin is an effective antitumor agent in hormone-refractory pr ostate cancer, but its mechanism(s) of action is not well understood. However, the properties of suramin as an agent which disrupts growth f actor action, and the importance of tumor-stroma interactions in prost ate tumor development and in HA synthesis led us to study the effect o f suramin on HA synthesis. Suramin inhibited HA synthesis by calf seru m-stimulated Swiss 3T3 fibroblasts at clinically relevant concentratio ns (IC50 = 183 mu g/mL). Increasing the serum concentration from 10 to 20% did not change the IC50 for HA synthesis, but increased the IC50 for [H-3]thymidine incorporation from 206 to 342 mu g/mL, indicating t hat the antiproliferative effect of suramin can be dissociated from it s effect on HA synthesis. Suramin did not alter the cellular concentra tions 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 8 00 mu g/mL. However, suramin treatment abolished the rise in HA synthe tase activity that follows the serum stimulation of quiescent 3T3 fibr oblasts in a concentration-dependent fashion, indicating an effect of suramin on the signal transduction pathways involved in the regulation of HA synthesis. These data suggest that one mechanism responsible fo r suramin's antitumor effect is to block tumor-associated HA synthesis , which is a component of tumor progression.