Utilizing hydrogen sulfide as a novel anti‐cancer agent by targeting cancer glycolysis and pH imbalance

Abstract

BACKGROUND AND PURPOSEMany disparate studies have reported the ambiguous role of hydrogen sulfide (H2S) in cell survival. The present study investigated the effect of H2S on the viability of cancer and non-cancer cells. EXPERIMENTAL APPROACHCancer and non-cancer cells were exposed to H2S [using sodium hydrosulfide (NaHS) and GYY4137] and cell viability was examined by crystal violet assay. We then examined cancer cellular glycolysis by in vitro enzymatic assays and pH regulator activity. Lastly, intracellular pH (pHi) was determined by ratiometric pHi measurement using BCECF staining. KEY RESULTSContinuous, but not a single, exposure to H2S decreased cell survival more effectively in cancer cells, as compared to non-cancer cells. Slow H2S-releasing donor, GYY4137, significantly increased glycolysis, leading to overproduction of lactate. H2S also decreased anion exchanger and sodium/proton exchanger activity. The combination of increased metabolic acid production and defective pH regulation resulted in an uncontrolled intracellular acidification, leading to cancer cell death. In contrast, no significant intracellular acidification or cell death was observed in non-cancer cells. CONCLUSIONS AND IMPLICATIONSLow and continuous exposure to H2S targets metabolic processes and pH homeostasis in cancer cells, potentially serving as a novel and selective anti-cancer strategy. Abbreviations

A Fast Hydrogen Sulfide–Releasing Donor Increases the Tumor Response to Radiotherapy

“…6C) in compensation to inhibition of the mitochondrial function. Supporting our findings, others have also reported that a synthetic H 2 S donor promotes an influx of glucose and triggers enhanced glycolysis in another human breast cancer cell line (31). We then analyzed the decreased proliferation induced by NaHS in the acidic condition.…”

“…By noticing that low pHe itself had profound impact on cancer cell proliferation, we questioned whether NaHS treatment was able to exacerbate the acidic stress experienced by cancer cells at low pHe. Indeed, it was recently evidenced that, besides its ability to enhance glycolysis, H 2 S also impairs the activity of pH regulators in cancer cells, leading to the intracellular accumulation of acid and reduction of pHi (31,32). It is also known that pHi must be kept in a narrow range, otherwise cell-cycle progression and biosynthetic processes are compromised (33).…”

Endogenous Hydrogen Sulfide Enhances Cell Proliferation of Human Gastric Cancer AGS Cells

“…It has been reported that the increased H 2 S production plays a crucial role in cell proliferation and the related angiogenesis in several types of cancer cell lines, such as colonic and ovarian cancers. 18,19) In addition, there are many papers showing that endogenous or exogenous H 2 S modulates cell proliferation and migration in gastric, oral, breast, pancreas, lung or prostate cancer and also leukemia, 12,[20][21][22] whereas, H 2 S promotes and suppresses cancer growth in distinct cells. Thus, the effects of H 2 S on cancers might vary with the tissues, conditions surrounding cancer, the amount of synthesized H 2 S, and so on.…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…Combined effects leading to increased metabolic acid production, defective pH regulation, and cell death. Lee et al (2014) 5.1. Cardiovascular system: Vascular smooth muscle and platelet function…”