gyy-4137 and Neoplasms

Though historically known as a toxic gas, hydrogen sulfide (H₂S) has displayed a new face as the third endogenous gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO). Here in this review, we survey the role and therapeutic potential of H₂S in cisplatin-induced nephrotoxicity. Specifically, reduction of H₂S by cystathionine γ-lyase (CSE) downregulation upon cisplatin treatment may contribute to cisplatin-induced renal cell injury, possibly by augmentation of endogenous reactive oxygen species (ROS) production, while H₂S donation may prevent subsequent renal dysfunction by inhibiting NADPH oxidase activation. Intriguingly, H₂S slow-releasing compound GYY4137 seems to increase the anticancer activity of cisplatin, at least in several cancer cell lines, and this is probably due to its own anticancer effect. However, the efficacy of H₂S donors in tumor-bearing animals remains to be tested in terms of renal protection and cancer inhibition after receiving cisplatin. Furthermore, accumulative evidence regarding usage of polysulfide, a novel H₂S derived molecule, in the therapy of cisplatin-induced nephrotoxicity, was also summarized.

Topics: Cisplatin; Cystathionine gamma-Lyase; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Sulfide; Kidney; Kidney Diseases; Morpholines; Neoplasms; Organothiophosphorus Compounds; Oxidation-Reduction; Reactive Oxygen Species; Smell

Hydrogen sulfide (H2S) is likely to join nitric oxide (NO) and carbon monoxide (CO) as the third gaseous transmitter, influencing an array of intracellular signaling cascades. Thus, H2S is implicated in numerous physiological processes and in the pathology of various diseases.. H2S-donating agents that liberate H2S slowly either alone or in combination with NO, the so-called NOSH compounds, are being synthesized, and these have been shown to have great potential against cancer.. An accurate determination of H2S levels is challenging. H2S and NO share many similar actions; do these similarities act to potentiate each other? Since many actions of H2S appear to be mediated through inhibition of inflammation and Nuclear factor kappa-light-chain-enhancer of activated B cells is a central player in this scenario, does S-nitrosylation of this transcription factor by NO affect its S-sulfhydration by H2S and vice versa?. Deciphering the molecular targets of these novel hybrid agents and having genetically engineered animals should help us move toward targeted therapeutic applications. Human safety data with these new hybrids is essential.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Hydrogen Sulfide; Morpholines; Neoplasms; Organothiophosphorus Compounds; Reactive Oxygen Species; Signal Transduction

Many disparate studies have reported the ambiguous role of hydrogen sulfide (H2 S) in cell survival. The present study investigated the effect of H2 S on the viability of cancer and non-cancer cells.. Cancer and non-cancer cells were exposed to H2 S [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.. Continuous, but not a single, exposure to H2 S decreased cell survival more effectively in cancer cells, as compared to non-cancer cells. Slow H2 S-releasing donor, GYY4137, significantly increased glycolysis, leading to overproduction of lactate. H2 S 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.. Low and continuous exposure to H2 S targets metabolic processes and pH homeostasis in cancer cells, potentially serving as a novel and selective anti-cancer strategy.

Topics: Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Survival; Glucose; Glycolysis; Humans; Hydrogen Sulfide; Hydrogen-Ion Concentration; Morpholines; Neoplasms; Organothiophosphorus Compounds; Sulfides