The dichotomous role of H2S in cancer cell biology? Déjà vu all over again

Abstract

Nitric oxide (NO) a gaseous free radical is one of the ten smallest molecules found in nature, while hydrogen sulfide (H₂S) is a gas that bears the pungent smell of rotten eggs. Both are toxic yet they are gasotransmitters of physiological relevance. There appears to be an uncanny resemblance between the general actions of these two gasotransmitters in health and disease. The role of NO and H₂S in cancer has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and antiinflammatory properties have been described. These paradoxes have been explained for both gasotransmitters in terms of each having a dual or biphasic effect that is dependent on the local flux of each gas. In this review/commentary, I have discussed the major roles of NO and H₂S in carcinogenesis, evaluating their dual nature, focusing on the enzymes that contribute to this paradox and evaluate the pros and cons of inhibiting or inducing each of these enzymes.

Keywords: CBS; CSE; Carcinogenesis; Hydrogen sulfide; Nitric oxide; iNOS.

Figure 1

Biosynthesis of nitric oxide and hydrogen sulfide. NO is produced by three nitric oxide synthase (NOS) isoforms: neuronal, endothelial, and inducible (nNOS, eNOS, and iNOS) that catalyze the oxidation of L-arginine to L-citrulline. NO is also produced through reduction of nitrite/nitrate under low oxygen conditions. H₂S is generated from oxidation of the substrates L- homocysteine, cystathionine, L-cysteine and 3-mercaptopyruvate through the enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). α-ketobutyrate, lanthionine, L-serine and pyruvate are the secondary products formed. Alternatively, production of H₂S occurs non-enzymatically from various storage forms of sulfur like thiosulfate, thiocysteine and sulfite. NO reacts with the active site of soluble guanylate cyclase (sGC) and produces cyclic GMP leading to vasorelaxation. Whereas H₂S raises cGMP levels through inhibition of phosphodiesterase 5A (PDE5A) an enzyme that catabolizes it. NO can affect cellular proteins by producing peroxynitrite which in turn can interact with cysteine residues to form S-nitrosothiols (RSNO). H₂S can also interact with sulfhydryl group of cysteines and proteins to form persulfides (R-SSH).

Figure 2

NO-H₂S cross-talk in the vascular tissue. H₂S decreases the expression level of NO-synthase (eNOS) in a cell-free system [128], while NO can either inhibit CBS activity in a cell free system [127] or increases the expression levels of CSE and CBS [11] to increase H₂S synthesis. H₂S activates eNOS by an Akt-dependent phosphorylation of the protein [132]. NO can interact with H₂S to form HSNO [138] and H₂S_n [139]; H₂S can interact with NO₂⁻ [124] or with RSNO [147, 148] to produce NO. H₂S decreases the sensitivity of the cGMP pathways and also it modifies K_Ca channels to decrease their sensitivity to NO. Solid arrows (blue) indicate stimulatory, while T-shaped arrows (red) indicate inhibitory inputs.

Figure 3

Chemical structures of selected NO-donating compounds. (A) NO-NSAIDs. (B) Activation of diazeniumdiolate prodrugs to release NO or HNO. (C) Structures of IPA/NO-aspirin and DEA/NO-aspirin. (D) JS-K; (E) PABA/NO and (F) RRx-001.

Figure 4

Synthetic H₂S-donating compounds. (A) GYY4137 a slow H₂S generating compound. (B) ADT (anethole dithiolethione); ADT-OH, (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, releases H₂S); (C) various H₂S-donating NSAIDs; (D) TBZ (4-hydroxy benzothiazamide, releases H₂S); (E) ATB-346, H₂S-donating naproxen; (F) ATB-429, H₂S-donating mesalamine; (G and H) NBS-1120 and NBS-1121, NOSH-aspirin, dual NO- and H₂S-donating hybrids of aspirin; (I) AVT-219, NOSH-naproxen, dual NO- and H₂S-donating hybrid of naproxen; (J) 3-butyl-1,2-dithiolane, releases H₂S.

Figure 5

(A) AP39, a mitochondrial-targeting H₂S-donor; (B) GIC-1001, trimebutine salt; (C) SG-1002, polyvalent sulfur.