title: ATB-346, a novel hydrogen sulfide-releasing anti-inflammatory drug, induces apoptosis of human melanoma cells and inhibits melanoma development in vivo.
abstract: Inflammation plays a key role in tumor promotion and development. Indeed, cyclooxygenase-2 (COX-2) expression is strongly associated with different types of cancer. An emerging class of compounds with significant anti-inflammatory properties is the hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs). They consist of a traditional NSAID to which an H2S-releasing moiety is covalently attached. We have recently demonstrated that H2S donors inhibit melanoma cell proliferation. In the current study, we evaluated the potential beneficial effects of a new H2S-releasing derivative of naproxen, ATB-346 [2-(6-methoxynapthalen-2-yl)-propionic acid 4-thiocarbamoyl phenyl ester] which inhibits COX activity but also releases H2S. We used cell culture and a mouse melanoma model to evaluate the effect of ATB-346 on: i) in vitro growth of human melanoma cells; ii) in vivo melanoma development in mice. Cell culture studies demonstrated that ATB-346 reduced the in vitro proliferation of human melanoma cells and this effect was associated to induction of apoptosis and inhibition of NF-κB activation. Moreover, ATB-346 had novel Akt signaling inhibitory properties. Daily oral dosing of ATB-346 (43μmol/kg) significantly reduced melanoma development in vivo. This study shows that ATB-346, a novel H2S-NSAID, inhibits human melanoma cell proliferation by inhibiting pro-survival pathways associated with NF-κB and Akt activation. Furthermore, oral treatment with ATB-346 inhibits melanoma growth in mice. In conclusion, the combination of inhibition of cyclooxygenase and delivery of H2S by ATB-346 may offer a promising alternative to existing therapies for melanoma.
authors: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors: Paola
authors: P
authors: De Cicco
authors: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors: Elisabetta
authors: E
authors: Panza
authors: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors: Giuseppe
authors: G
authors: Ercolano
authors: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors: Chiara
authors: C
authors: Armogida
authors: Department of Experimental Oncology, National Cancer Institute, G. Pascale, Naples, Italy.
authors: Giuseppe
authors: G
authors: Sessa
authors: Department of Experimental Oncology, National Cancer Institute, G. Pascale, Naples, Italy.
authors: Giuseppe
authors: G
authors: Pirozzi
authors: Department of Pharmacy, University of Naples Federico II, Naples, Italy. Electronic address: cirino@unina.it.
authors: Giuseppe
authors: G
authors: Cirino
authors: Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors: John L
authors: JL
authors: Wallace
authors: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors: Angela
authors: A
authors: Ianaro
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000276:immunology; D005260:Female; D006801:Humans; D006862:Hydrogen Sulfide / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D009288:Naproxen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C550692:2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D018925:Chemokines; D016328:NF-kappa B; D009288:Naproxen; D006862:Hydrogen Sulfide
keywords: Apoptosis; Cyclooxygenase inhibitor; Hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs; Melanoma