Anti-metastatic Properties of Naproxen-HBTA in a Murine Model of Cutaneous Melanoma.

The beneficial effects of H(2)S-release and of COXs-inhibition have been exploited in the design of novel anti-inflammatory drugs, the H(2)S-releasing non-steroidal anti-inflammatory drugs (H(2)S-NSAIDs), showing promising potential for chemoprevention in cancers. Here, we evaluated the efficacy of a new H(2)S-releasing derivative of naproxen, named naproxen-4-hydroxybenzodithioate (naproxen-HBTA), in reducing metastatic melanoma features, both in vitro and in vivo. The novel H(2)S donor has been prepared following a synthetic scheme that provided high yields and purity. In particular, we investigated the effect of naproxen-HBTA in vitro on several metastatic features of human melanoma cells such as proliferation, migration, invasion, and colonies formation and in vivo in a model of cutaneous melanoma. Cell culture studies demonstrated that naproxen-HBTA induced caspase 3-mediated apoptosis and inhibited motility, invasiveness, and focus formation. Finally, daily oral treatment with naproxen-HBTA significantly suppressed melanoma growth and progression in mice. In conclusion, by using this dual approach we propose that the COX-2 and H(2)S pathways could be regarded as novel therapeutic targets/tools to generate new treatment options based on "combination therapy" for melanoma.