Endogenous hydrogen sulfide inhibition suppresses tumor growth by promoting apoptosis and pyroptosis in esophageal cancer cells.

BACKGROUND: Hydrogen sulfide (H2S) has been identified as the third gaseous signaling molecule. Endogenous H2S plays a key role in the progression of various types of cancer. However, the effect of endogenous H2S on the growth of esophageal cancer (EC) remains unknown. METHODS: In this study, three kinds of H2S-producing enzymes inhibitors, DL-propargylglycine (PAG, inhibitor of cystathionine-γ-lyase), aminooxyacetic acid (AOAA, inhibitor of cystathionine-ß-synthase), and L-aspartic acid (L-Asp, inhibitor of 3-mercaptopyruvate sulfurtransferase) were used to determine the role of endogenous H2S in the growth of EC9706 and K450 human EC cells. RESULTS: The results indicated that the combination (PAG+AOAA+L-Asp) group showed higher inhibitory effects on the viability, proliferation, migration, and invasion of EC cells than PAG, AOAA, and L-Asp group. Inhibition of endogenous H2S promoted apoptosis via activation of mitogen-activated protein kinase pathway in EC cells. Endogenous H2S suppression triggered pyroptosis of EC cells by activating reactive oxygen species-mediated nuclear factor-κB signaling pathway. In addition, the combine group showed its more powerful growth-inhibitory effect on the growth of human EC xenograft tumors in nude mice without obvious toxicity. CONCLUSION: Our results indicate that inhibition of endogenous H2S production can significantly inhibit human EC cell growth via promotion of apoptosis and pyroptosis. Endogenous H2S may be a promising therapeutic target in EC cells. Novel inhibitors for H2S-producing enzymes can be designed and developed for EC treatment.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-ß-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

Role of hydrogen sulphide in physiological and pathological angiogenesis.

The role of hydrogen sulphide (H2 S) in angiogenesis has been widely demonstrated. Vascular endothelial growth factor (VEGF) plays an important role in H2 S-induced angiogenesis. H2 S promotes angiogenesis by upregulating VEGF via pro-angiogenic signal transduction. The involved signalling pathways include the mitogen-activated protein kinase pathway, phosphoinositide-3 kinase pathway, nitric oxide (NO) synthase/NO pathway, signal transducer and activator of transcription 3 (STAT3) pathway, and adenosine triphosphate (ATP)-sensitive potassium (KATP ) channels. H2 S has been shown to contribute to tumour angiogenesis, diabetic wound healing, angiogenesis in cardiac and cerebral ischaemic tissues, and physiological angiogenesis during the menstrual cycle and pregnancy. Furthermore, H2 S can exert an anti-angiogenic effect by inactivating Wnt/ß-catenin signalling or blocking the STAT3 pathway in tumours. Therefore, H2 S plays a double-edged sword role in the process of angiogenesis. The regulation of H2 S production is a promising therapeutic approach for angiogenesis-associated diseases. Novel H2 S donors and/or inhibitors can be developed in the treatment of angiogenesis-dependent diseases.

Cystathionine ß-Synthase Regulates the Proliferation, Migration, and Invasion of Thyroid Carcinoma Cells.

Thyroid cancer is considered to be one of the most common endocrine tumors worldwide. Cystathionine ß-synthase (CBS) plays a crucial role in the occurrence of several types of malignancies. And yet, the mechanism of action of CBS in the growth of thyroid carcinoma cells is still unrevealed. We found that CBS level in thyroid carcinoma tissue was higher than that in adjacent normal tissue. The overexpression of CBS enhanced the proliferation, migration, and invasion of thyroid cancer cells, while the downregulation of CBS exerted reverse effects. CBS overexpression reduced the levels of cleaved caspase-3 and cleaved poly ADP-ribose polymerase in thyroid cancer cells, whereas CBS knockdown showed reverse trends. CBS overexpression decreased reactive oxygen species (ROS) levels but increased the levels of Wnt3a and phosphorylations of phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT), mammalian target of rapamycin (mTOR), ß-catenin, and glycogen synthase kinase-3 beta, while CBS knockdown exerted opposite effects. In addition, CBS overexpression promoted the growth of xenografted thyroid carcinoma, whereas CBS knockdown decreased the tumor growth by modulating angiogenesis, cell cycle, and apoptosis. Furthermore, aminooxyacetic acid (an inhibitor of CBS) dose-dependently inhibited thyroid carcinoma cell growth. CBS can regulate the proliferation, migration, and invasion of human thyroid cancer cells via ROS-mediated PI3K/AKT/mTOR and Wnt/ß-catenin pathways. CBS can be a potential biomarker for diagnosing or prognosing thyroid carcinoma. Novel donors that inhibit the expression of CBS can be developed in the treatment of thyroid carcinoma.

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases.

Hydrogen sulfide (H2S) has long been considered as a toxic gas, but as research progressed, the idea has been updated and it has now been shown to have potent protective effects at reasonable concentrations. H2S is an endogenous gas signaling molecule in mammals and is produced by specific enzymes in different cell types. An increasing number of studies indicate that H2S plays an important role in cardiovascular homeostasis, and in most cases, H2S has been reported to be downregulated in cardiovascular diseases (CVDs). Similarly, in preclinical studies, H2S has been shown to prevent CVDs and improve heart function after heart failure. Recently, many H2S donors have been synthesized and tested in cellular and animal models. Moreover, numerous molecular mechanisms have been proposed to demonstrate the effects of these donors. In this review, we will provide an update on the role of H2S in cardiovascular activities and its involvement in pathological states, with a special focus on the roles of exogenous H2S in cardiac protection.