Hydrogen Sulfide (H₂S): As a Potent Modulator and Therapeutic Prodrug in Cancer

Abstract

Hydrogen sulfide (H2S) is an endogenous gaseous molecule present in all living organisms and has been traditionally studied for its toxicity. Interestingly, increased understanding of H2S effects in organ physiology has recently shown its relevance as a signalling molecule, with potentially important implications in variety of clinical disorders, including cancer. H2S is primarily produced in mammalian cells under various enzymatic pathways. A developing focus of H2S is a blooming hotspot that studies chemical, biological mechanisms, and therapeutic effects of H2S. Herein, we describe the physiological and biochemical properties of H2S, the enzymatic pathways leading to its endogenous production and its catabolic routes. In addition, we discuss the role of currently known H2S-releasing agents, or H2S donors, including their potential as therapeutic tools. Then we illustrate the mechanisms known to support the pleiotropic effects of H2S, with a particular focus on persulfhydration, which plays a key role in H2S-mediating signalling pathways. We then address the paradoxical role played by H2S in tumour biology and discuss the potential of exploiting H2S levels as novel cancer biomarkers and diagnostic tools. Finally, we describe the most recent preclinical applications focused on assessing the anti-cancer impact of most common H2S-releasing compounds. While the evidence in favour of H2S as an alternative cancer therapy in the field of translational medicine is yet to be clearly provided, application of H2S is emerging as potent anticancer therapies in preclinical trails.

The double-edged sword role of hydrogen sulfide in hepatocellular carcinoma

“…The evidence indicates that H 2 S plays a vital role in multiple pathological and physiological processes, such as anti-inflammation ( Mohammed et al, 2021 ), anti-apoptosis ( Fouad et al, 2020 ), anti-oxidative stress ( Tocmo and Parkin, 2019 ), blood pressure reduction ( Greaney et al, 2017 ; Zaorska et al, 2019 ), and the regulation of cell survival/death, cell proliferation/hypertrophy and cell differentiation ( Zhang et al, 2017 ). Hence, H 2 S participates in many diseases, such as lung diseases ( Pacitti et al, 2021 ), ischemia/reperfusion injury ( Krylatov et al, 2021 ), and cancers ( Shackelford et al, 2021b ; Khattak et al, 2022 ; Faris et al, 2023 ). In recent years, many studies have revealed that H 2 S has the dual effects of anticancer and cancer promotion in HCC, but the relevant mechanisms are not completely understood.…”

The therapeutic potential for targeting CSE/H2S signaling in macrophages against Escherichia coli infection

“…Hydrogen sulfide (hereafter referred to as H 2 S) the latest identified endogenous gaseous mediator, was once considered a foul-smelling and hazardous gas found in the environment [ 9 ]. Recently, H 2 S has gained increasing attention as an important player in modulating a wide range of physiological and pathological conditions [ 10 , 11 ]. In mammals, similar to NO and CO, three enzymes including cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and the 3-mercaptopyruvate sulphur transferase (3-MPST) are responsible for H 2 S generation.…”