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 μg/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 μg/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 μg/mL. However, suramin treatment abolished the rise in HA synthetase activity that follows the serum stimulation of quiescent 3T3 fibroblasts 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 for suramin's antitumor effect is to block tumor-associated HA synthesis, which is a component of tumor progression.