Review H 2 S-releasing drugs: Anti-inflammatory, cytoprotective and chemopreventative potential Burcu Gemici a , Wagdi Elsheikh b , Karla B. Feitosa c , Soraia K.P. Costa c , Marcelo N. Muscara c , John L. Wallace d,e, * a Near East University, Nicosia, Cyprus b Department of Medicine, McMaster University, Hamilton, Ontario, Canada c Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo 05508-000, SP, Brazil d Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada e Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada ARTICLE INFO Article history: Available online 18 November 2014 Keywords: Gastrointestinal Cytoprotection Inflammation Hydrogen sulfide Drug development A B ST R AC T Hydrogen sulfide exerts a number of cytoprotective and anti-inflammatory effects in many organ systems. In an effort to exploit these potent and beneficial effects, a number of hydrogen sulfide-releasing de- rivatives of existing drugs have been developed and extensively tested in pre-clinical models. In particular, efforts have been made by several groups to develop hydrogen sulfide-releasing derivatives of a number of nonsteroidal anti-inflammatory drugs. The main goal of this approach is to reduce the gastrointesti- nal ulceration and bleeding caused by this class of drugs, particularly when used chronically such as in the treatment of arthritis. However, these drugs may also have utility for prevention of various types of cancer. This paper provides an overview of some of the mechanisms underlying the anti-inflammatory and cytoprotective actions of hydrogen sulfide. It also gives some examples of hydrogen sulfide- releasing anti-inflammatory drugs, and their actions in terms of reducing inflammation and attenuating the development of cancer in experimental models. © 2014 Elsevier Inc. All rights reserved. Contents 1. Introduction ........................................................................................................................................................................................................................................................... 25 2. Anti-inflammatory and pro-resolution effects of hydrogen sulfide ................................................................................................................................................... 26 3. Cytoprotective actions of hydrogen sulfide in GI tract ........................................................................................................................................................................... 26 4. GI-sparing anti-inflammatory drugs ............................................................................................................................................................................................................. 27 5. Chemopreventative actions of H2S-releasing NSAIDs ............................................................................................................................................................................. 29 6. Future directions .................................................................................................................................................................................................................................................. 30 References .............................................................................................................................................................................................................................................................. 30 1. Introduction Over the past decade, several novel H2S-based drugs have been described [1,2]. Several of the most advanced such compounds are derivatives of currently used anti-inflammatory drugs. The H2S-releasing drugs show greatly reduced toxicity (particularly in the GI tract) and, in some cases, improved efficacy. Several nonste- roidal anti-inflammatory drugs (NSAIDs) have been found to substantially reduce the incidence of several types of human cancers, but their adverse effects preclude their use for these indications, which would require long-term exposure to the drugs. H2S itself exerts potent anti-inflammatory effects [3] and, in some test systems, anti-cancer effects [4,5]. In this article, we describe some of the fea- tures of H2S-releasing drugs that we have developed with respect Abbreviations: ATP, adenosine triphosphate; COX, cyclooxygenase; CSE, cysta- thionine ϒ-lyase; GI, gastrointestinal; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; LFA, lymphocyte function-associated antigen; NFĸB, nuclear factor ĸB; Nrf2, nuclear factor erythroid 2-related factor 2; NSAID, nonsteroidal anti- inflammatory drug; PG, prostaglandin; TNF, tumour necrosis factor. Declaration: Dr. Wallace is the founder and a director of Antibe Therapeutics Inc., which is developing H2S-releasing anti-inflammatory drugs. * Corresponding author. 15 Prince Arthur Avenue, Toronto, Ontario, Canada M5R 1B2. E-mail address: altapharm@hotmail.com (J.L. Wallace). http://dx.doi.org/10.1016/j.niox.2014.11.010 1089-8603/© 2014 Elsevier Inc. All rights reserved. Nitric Oxide 46 (2015) 25–31 Contents lists available at ScienceDirect Nitric Oxide journal homepage: www.elsevier.com/locate/yniox