S-nitrosothiols and H2S donors: Potential chemo-therapeutic agents in cancer

Abstract

Nitric Oxide (NO) and Hydrogen Sulfide (H2S) are components of an “interactome”, which is defined as a redox system involving the interactions of RSS, RNS and ROS. Chemical interaction by these species is common and is characterized by one and two electron oxidation, nitrosylation, nitration and sulfuration/polysulfidation reactions. NO and H2S are gases that penetrate cell membranes, are synthesized by specific enzymes, are ubiquitous, regulate protein activities through post-translational modifications and participate in cell signaling. The two molecules at high concentrations compared to physiological concentrations may result in cellular damage particularly through their interaction with other reactive species. NO and H2S can interact with each other and form a variety of molecular species which may have constructive or destructive behavior depending on the cell type, the cellular environment (ex. oxygen tension, pH, redox state), where the products are produced and in what concentrations. Cross talk exists between NO and H2S, whereby they can influence the generation and signaling behavior of each other. Given the above mentioned properties of NO and H2S and studies in cancer cells and animal models employing NO and H2S donors that generate higher than physiological concentrations of NO and H2S and are effective in killing cancer cells but not normal cells, lend credence to the possibility of the utility of these donors in an approach to the treatment of cancer.

The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives

“…It is noteworthy that either stable NRF2 knockdown or glutaminolysis inhibition with CB-839 markedly enhanced the sensitivity of PDAC cells to gemcitabine, and the anticancer effect was further potentiated when CB839 was used in combination with gemcitabine in in vivo experiments [115]. Taken together, these data have indicated that NRF2 actively participates in the regulation of glutamine metabolism in malignant tumors suggesting that alterations in the KEAP1/NRF2 signaling alone or in combination with concomitant oncogenic activation might uncover specific metabolic vulnerabilities that might be therapeutically targeted to treat otherwise resistant tumors [116].…”

Hydrogen Sulfide, an Endogenous Stimulator of Mitochondrial Function in Cancer Cells

“…), exogenously administered H 2 S donors reach high local concentrations, which are cytotoxic to cancer cells (but also to any other cell type) ( Figure 2 ). The various chemical classes of anticancer H 2 S donors, their cellular actions (which, in some cases include the initiation of mitochondrial cell death pathways), and the potential difficulties with testing and developing such compounds (e.g., the theoretical and practical problems around selective targeting of the tumor cells with H 2 S donors in vivo) are extensively discussed in specialized reviews [ 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ] and will not be reiterated in the current article.…”

Role of hydrogen sulfide donors in cancer development and progression

“…To date, numerous H 2 S releasing drugs with different properties, donating mechanisms, and capabilities have been synthesized for experimental use. With the exception of their molecular targets, the anti-cancer effects of H 2 S donors have been extensively reviewed [26][27][28][29]. Herein, we will summarize recent findings on the roles of H 2 S donors in cancer management by illuminating their molecular targets, mechanisms involved and their downstream effects in cellular activities.…”