AUTHOR=Ercolano Giuseppe , De Cicco Paola , Frecentese Francesco , Saccone Irene , Corvino Angela , Giordano Flavia , Magli Elisa , Fiorino Ferdinando , Severino Beatrice , Calderone Vincenzo , Citi Valentina , Cirino Giuseppe , Ianaro Angela 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00066

DOI=10.3389/fphar.2019.00066

ISSN=1663-9812

ABSTRACT=<p>The beneficial effects of H<sub>2</sub>S-release and of COXs-inhibition have been exploited in the design of novel anti-inflammatory drugs, the H<sub>2</sub>S-releasing non-steroidal anti-inflammatory drugs (H<sub>2</sub>S-NSAIDs), showing promising potential for chemoprevention in cancers. Here, we evaluated the efficacy of a new H<sub>2</sub>S-releasing derivative of naproxen, named naproxen-4-hydroxybenzodithioate (naproxen-HBTA), in reducing metastatic melanoma features, both <italic>in vitro</italic> and <italic>in vivo</italic>. The novel H<sub>2</sub>S donor has been prepared following a synthetic scheme that provided high yields and purity. In particular, we investigated the effect of naproxen-HBTA <italic>in vitro</italic> on several metastatic features of human melanoma cells such as proliferation, migration, invasion, and colonies formation and <italic>in vivo</italic> 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<sub>2</sub>S pathways could be regarded as novel therapeutic targets/tools to generate new treatment options based on “combination therapy” for melanoma.</p>