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

Abstract

The beneficial effects of H2S-release and of COXs-inhibition have been exploited in the design of novel anti-inflammatory drugs, the H2S-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs), showing promising potential for chemoprevention in cancers. Here, we evaluated the efficacy of a new H2S-releasing derivative of naproxen, named naproxen-4-hydroxybenzodithioate (naproxen-HBTA), in reducing metastatic melanoma features, both in vitro and in vivo. The novel H2S 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 H2S pathways could be regarded as novel therapeutic targets/tools to generate new treatment options based on “combination therapy” for melanoma.

Hydrogen sulfide and dermatological diseases

“…Furthermore, oral administration of ATB‐346 (43 μmol·kg −1 ) to mice resulted in significant growth delay of the melanoma tumours (up to 70%), without affecting body weight (De Cicco et al, ). In a recently published study from the same group, Ercolano et al () show that another H 2 S‐releasing naproxen derivative, naproxen‐4‐hydroxybenzodithioate (naproxen‐HBTA; at 10 and 30 μM; Figure ), induced caspase 3‐mediated apoptosis and inhibited human melanoma cell proliferation, migration, invasion, and colony formation in vitro. In addition, the authors also show the beneficial effects, in vivo, of this H 2 S‐releasing naproxen derivative, as the daily oral treatment of mice with 14.5 mg·kg −1 of naproxen‐HBTA resulted in significant suppression of melanoma growth and progression.…”

Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches

“…A similar investigation on in vitro models of macrophages and in vivo fat-fed apoE − / − mice was carried out also with a particular class of H 2 S-donor, i.e. the H 2 S-donors hybrids [78] , [79] , [80] , [81] . These compounds were synthesized on the basis of previous experience on the NO-donor hybrids, in order to confer the positive effects of the gasotransmitter to selected native molecules.…”

Trends in H2S-Donors Chemistry and Their Effects in Cardiovascular Diseases

“…Thus, in order to obtain effective H 2 S donors with controllable release rates, a series of N-(benzoylthio)benzamides [ 49 ], acyl perthiols [ 50 , 51 ], arylthioamides [ 52 ], 1,2,4-thiadiazolidin-3,5-diones [ 53 ], iminothioethers [ 54 ], mercaptopyruvate [ 55 ], dithioates [ 56 ], isothiocyanate [ 57 , 58 ], and thiocarbamates [ 59 ] were developed and evaluated for their H 2 S-releasing properties.…”