HYDROGEN SULFIDE (H2S) DONOR AS AN ANTI-CANCER AGENT: TARGETING GLUCOSE METABOLISM AND PHI IMBALANCE TO ANTI-CANCER CELL VIABILITY, METASTASIS AND ANGIOGENESIS

Abstract

Hydrogen sulfide (H2S) is an important gasotransmitter exhibits many physiological and pathophysiological functions. In current study, we showed that continual exposure of NaHS at low micromolar concentrations selectively exhibited cytotoxicity on cancer but not non-cancer cells. Using a synthetic slow-releasing H2S donor GYY4137, we observed H2S induced increased glucose uptake, increased glucose utilization and increased lactate production in cancer cells. Furthermore, an impaired pH regulator activity was also evidenced. The combined effects of high glycolysis and defective pH regulation led to significant intracellular acidification that triggered cancer cell death. Furthermore, we demonstrated invasive cancers exhibited glycolytic adaptation and perturbation on intracellular lactate accumulation enhanced their sensitivity to H2S. Cancer metastasis and cancer-activated angiogenesis were inhibited by H2S treatment. This study showed that H2S targeting on glycolytic metabolism and pHi imbalance of cancer and cancer-activated endothelial cells warrants development of H2S-based donor as an innovative cancer therapeutic strategy.