Effect of pharmacological inhibition of endogenous hydrogen sulfide production on bladder cancer progression
Abstract
Present bladder cancer therapies have extremely limited therapeutic impact giving it the highest lifetime treatment cost per patient and leading to an imperative need for investigation of novel therapies. Recent literature suggests hydrogen sulfide (H2S), an endogenously produced gaseous signaling molecule, plays a pivotal role in cancer pathophysiology. This study investigated the effect of inhibiting endogenous H2S production on bladder cancer progression. We targeted the H2S-producing enzyme, cystathionine -lyase (CSE), and found that inhibiting its activity significantly attenuated 5637 and MB49 bladder cancer cell viability. Furthermore, an intravesical murine model of bladder cancer was subjected to single and combination intravesical therapies consisting of the CSE inhibitor, propargylglycine (PAG), and gemcitabine (GEM) chemotherapy followed by evaluation of tumor response via magnetic resonance imaging, pathology, and immunohistochemical staining. We observed a significant attenuation of tumor growth and invasion following CSE inhibition and enhanced anti-cancer effects of GEM by PAG, resulting in tumor regression and abrogation of invasion. Our findings suggest that inhibition of endogenous H2S production induced apoptosis and an immune response and attenuated VEGF-led neovascularization and proliferation within the bladder tumor. It also enhanced the pro-apoptotic and anti-neovascularization effects of GEM. Therefore, inhibition of endogenous H2S production may have antineoplastic potential as well as additive effect with conventional chemotherapy on bladder cancer progression, suggesting H2S as a novel target for developing improved combination therapies against bladder cancer.