Therapeutic application of hydrogen sulfide donors: the potential and challenges

Abstract

Hydrogen sulfide (H₂S), a colorless gas smelling of rotten egg, has long been considered a toxic gas and environment hazard. However, evidences show that H₂S plays a great role in many physiological and pathological activities, and it exhibits different effects when applied at various doses. In this review, we summarize the chemistry and biomedical applications of H₂S-releasing compounds, including inorganic salts, phosphorodithioate derivatives, derivatives of Allium sativum extracts, derivatives of thioaminoacids, and derivatives of anti-inflammatory drugs.

Keywords

hydrogen sulfide / cardiovascular / cancer / hypertension

References

[1] Szabó C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 2007; 6(11): 917–935

[2] Wang R. Two’s company, three’s a crowd: can H₂S be the third endogenous gaseous transmitter? FASEB J 2002; 16(13): 1792–1798

[3] Kamoun P. Endogenous production of hydrogen sulfide in mammals. Amino Acids 2004; 26(3): 243–254 doi:10.1007/s00726-004-0072-x

[4] Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. Selectivity of commonly used pharmacological inhibitors for cystathionine b synthase (CBS) and cystathionine g lyase (CSE). Br J Pharmacol 2013; 169(4): 922–932 doi:10.1111/bph.12171

[5] Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 2008; 322(5901): 587–590PMID:18948540

[6] Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 2012; 92(2): 791–796

[7] Whiteman M, Le Trionnaire S, Chopra M, Fox B, Whatmore J. Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools. Clin Sci (Lond) 2011; 121(11): 459–488

[8] Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J. Structural basis for the inhibition mechanism of human cystathionine γ-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem 2009; 284(5): 3076–3085

[9] Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. Selectivity of commonly used pharmacological inhibitors for cystathionine b synthase (CBS) and cystathionine g lyase (CSE). Br J Pharmacol 2013; 169(4): 922–932

[10] Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 2001; 20(21): 6008–6016

[11] Kashfi K, Olson KR. Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras. Biochem Pharmacol 2013; 85(5): 689–703

[12] Takeuchi H, Setoguchi T, Machigashira M, Kanbara K, Izumi Y. Hydrogen sulfide inhibits cell proliferation and induces cell cycle arrest via an elevated p21 Cip1 level in Ca9-22 cells. J Periodontal Res 2008; 43(1): 90–95

[13] Yan H, Du J, Tang C. The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats. Biochem Biophys Res Commun 2004; 313(1): 22–27

[14] Ariyaratnam P, Loubani M, Morice AH. Hydrogen sulphide vasodilates human pulmonary arteries: a possible role in pulmonary hypertension? Microvasc Res 2013; 90: 135–137

[15] Holwerda KM, Burke SD, Faas MM, Zsengeller Z, Stillman IE, Kang PM, van Goor H, McCurley A, Jaffe IZ, Karumanchi SA, Lely AT. Hydrogen sulfide attenuates sFlt1-induced hypertension and renal damage by upregulating vascular endothelial growth factor. J Am Soc Nephrol 2014; 25(4): 717–725

[16] Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA 2007; 104(46): 17977–17982

[17] Rodriguez J, Maloney RE, Rassaf T, Bryan NS, Feelisch M. Chemical nature of nitric oxide storage forms in rat vascular tissue. Proc Natl Acad Sci USA 2003; 100(1): 336–341

[18] Kondo K, Bhushan S, King AL, Prabhu SD, Hamid T, Koenig S, Murohara T, Predmore BL, Gojon G Sr, Gojon G Jr, Wang R, Karusula N, Nicholson CK, Calvert JW, Lefer DJ. H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation 2013; 127(10): 1116–1127

[19] Klocke R, Tian W, Kuhlmann MT, Nikol S. Surgical animal models of heart failure related to coronary heart disease. Cardiovasc Res 2007; 74(1): 29–38

[20] Zunnunov ZR. Efficacy and safety of hydrogen sulfide balneotherapy in ischemic heart disease the arid zone. Ter Arkh 2004; 76(8): 15–18 (in Russian)

[21] Liu Z, Han Y, Li L, Lu H, Meng G, Li X, Shirhan M, Peh MT, Xie L, Zhou S, Wang X, Chen Q, Dai W, Tan CH, Pan S, Moore PK, Ji Y. The hydrogen sulfide donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E(-/-) mice. Br J Pharmacol 2013; 169(8): 1795–1809

[22] Huang Y, Li F, Tong W, Zhang A, He Y, Fu T, Liu B. Hydrogen sulfide, a gaseous transmitter, stimulates proliferation of interstitial cells of Cajal via phosphorylation of AKT protein kinase. Tohoku J Exp Med 2010; 221(2): 125–132

[23] Toombs CF, Insko MA, Wintner EA, Deckwerth TL, Usansky H, Jamil K, Goldstein B, Cooreman M, Szabo C. Detection of exhaled hydrogen sulphide gas in healthy human volunteers during intravenous administration of sodium sulphide. Br J Clin Pharmacol 2010; 69(6): 626–636

[24] Lee ZW, Zhou J, Chen CS, Zhao Y, Tan CH, Li L, Moore PK, Deng LW. The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. PLoS ONE 2011; 6(6): e21077

[25] Li L, Whiteman M, Guan YY, Neo KL, Cheng Y, Lee SW, Zhao Y, Baskar R, Tan CH, Moore PK. Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 2008; 117(18): 2351–2360

[26] Li L, Salto-Tellez M, Tan CH, Whiteman M, Moore PK. GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free Radic Biol Med 2009; 47(1): 103–113

[27] Lee ZW, Teo XY, Tay EYW, Tan CH, Hagen T, Moore PK, Deng LW. Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance. Br J Pharmacol 2014; 171(18): 4322–4336

[28] Tang FY, Chiang EP, Pai MH. Consumption of S-allylcysteine inhibits the growth of human non-small-cell lung carcinoma in a mouse xenograft model. J Agric Food Chem 2010; 58(20): 11156–11164

[29] Ried K, Frank OR, Stocks NP. Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: a randomised controlled trial. Maturitas 2010; 67(2): 144–150

[30] Chuah SC, Moore PK, Zhu YZ. S-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. Am J Physiol Heart Circ Physiol 2007; 293(5): H2693–H2701

[31] Wang Q, Wang XL, Liu HR, Rose P, Zhu YZ. Protective effects of cysteine analogues on acute myocardial ischemia: novel modulators of endogenous H2S production. Antioxid Redox Signal 2010; 12(10):1155–1165. doi: 10.1089/ars.2009.2947 PMID: 19842912

[32] Kan J, Guo W, Huang C, Bao G, Zhu Y, Zhu YZ. S-propargyl-cysteine, a novel water-soluble modulator of endogenous hydrogen sulfide, promotes angiogenesis through activation of signal transducer and activator of transcription 3. Antioxid Redox Signal 2014; 20(15): 2303–2316

[33] Pan LL, Liu XH, Gong QH, Zhu YZ. S-Propargyl-cysteine (SPRC) attenuated lipopolysaccharide-induced inflammatory response in H9c2 cells involved in a hydrogen sulfide-dependent mechanism. Amino Acids 2011; 41(1): 205–215

[34] Gong QH, Wang Q, Pan LL, Liu XH, Xin H, Zhu YZ. S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NF-kB pathway in rats. Brain Behav Immun 2011; 25(1): 110–119

[35] Ma K, Liu Y, Zhu Q, Liu CH, Duan JL, Tan BK, Zhu YZ. H₂S donor, S-propargyl-cysteine, increases CSE in SGC-7901 and cancer-induced mice: evidence for a novel anti-cancer effect of endogenous H₂S? PLoS ONE 2011; 6(6): e20525

[36] Liu C, Gu X, Zhu YZ. Synthesis and biological evaluation of novel leonurine-SPRC conjugate as cardioprotective agents. Bioorg Med Chem Lett 2010; 20(23): 6942–6946

[37] Amagase H. Clarifying the real bioactive constituents of garlic. J Nutr 2006; 136(3 Suppl): 716S–725S

[38] Yun HM, Ban JO, Park KR, Lee CK, Jeong HS, Han SB, Hong JT. Potential therapeutic effects of functionally active compounds isolated from garlic. Pharmacol Ther 2014; 142(2): 183–195

[39] Kalra N, Arora A, Shukla Y. Involvement of multiple signaling pathways in diallyl sulfide mediated apoptosis in mouse skin tumors. Asian Pac J Cancer Prev 2006; 7(4): 556–562

[40] Wu PP, Liu KC, Huang WW, Chueh FS, Ko YC, Chiu TH, Lin JP, Kuo JH, Yang JS, Chung JG. Diallyl trisulfide (DATS) inhibits mouse colon tumor in mouse CT-26 cells allograft model in vivo. Phytomedicine 2011; 18(8-9): 672–676

[41] Filomeni G, Aquilano K, Rotilio G, Ciriolo MR. Reactive oxygen species-dependent c-Jun NH₂-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. Cancer Res 2003; 63(18): 5940–5949

[42] Zhou Z, von Wantoch Rekowski M, Coletta C, Szabo C, Bucci M, Cirino G, Topouzis S, Papapetropoulos A, Giannis A. Thioglycine and L-thiovaline: biologically active H₂S-donors. Bioorg Med Chem 2012; 20(8): 2675–2678

[43] Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S. Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology 2007; 132(1): 261–271

[44] Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002; 94(4): 252–266

[45] Chattopadhyay M, Kodela R, Nath N, Dastagirzada YM, Velázquez-Martínez CA, Boring D, Kashfi K. Hydrogen sulfide-releasing NSAIDs inhibit the growth of human cancer cells: a general property and evidence of a tissue type-independent effect. Biochem Pharmacol 2012; 83(6): 715–722

[46] Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 1996; 52(2): 237–245

[47] Kodela R, Chattopadhyay M, Kashfi K. NOSH-aspirin: a novel nitric oxide-hydrogen sulfide-releasing hybrid: a new class of anti-inflammatory pharmaceuticals. ACS Med Chem Lett 2012; 3(3): 257–262

[48] Zhao Y, Wang H, Xian M. Cysteine-activated hydrogen sulfide (H₂S) donors. JACS 2011;133 (1) 15–17 DOI: 10.1021/ja1085723

[49] Zhao Y, Bhushan S, Yang C, Otsuka H, Stein JD, Pacheco A, Peng B, Devarie-Baez NO, Aguilar HC, Lefer DJ, Xian M. Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury. ACS Chem Biol 2013; 8(6): 1283–1290

[50] Chen WS, Zang QG, Wang LQ, Tang FY, Han YJ, Yang CJ, Deng L, Liu YN. NIR light controlled release of caged hydrogen sulfide based on upconversion nanoparticles. Chem Commun 2015; 51:9193–9196 DOI: 10.1039/C5CC02508G

[51] Eghbal MA, Pennefather PS, O’Brien PJ. H₂S cytotoxicity mechanism involves reactive oxygen species formation and mitochondrial depolarisation. Toxicology 2004; 203(1-3): 69–76

[52] Huang C, Kan J, Liu X, Ma F, Tran BH, Zou Y, Wang S, Zhu YZ. Cardioprotective effects of a novel hydrogen sulfide agent-controlled release formulation of S-propargyl-cysteine on heart failure rats and molecular mechanisms. PLoS ONE 2013; 8(7): e69205doi: 10.1371/journal.pone.0069205

[53] Han Y, Qin J, Chang X, Yang Z, Du J. Hydrogen sulfide and carbon monoxide are in synergy with each other in the pathogenesis of recurrent febrile seizures. Cell Mol Neurobiol 2006; 26(1): 101–107

[54] Wang YF, Shi LN, Du JB, Tang CS. Impact of L-arginine on hydrogen sulfide/cystathionine-γ-lyase pathway in rats with high blood flow-induced pulmonary hypertension. Biochem Biophys Res Commun 2006; 345(2): 851–857

[55] Whiteman M, Li L, Kostetski I, Chu SH, Siau JL, Bhatia M, Moore PK. Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun 2006; 343(1): 303–310

[56] Ryter SW, Alam J, Choi AMK. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006; 86(2): 583–650

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg