Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Sener, Alp

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.

Summary for Lay Audience

Bladder cancer is the 10th most common cancer worldwide with almost 600,000 new cases and over 200,000 associated deaths occurring in 2020 alone. Current bladder cancer therapies are inadequate and associated with high failure and complication rates, lengthy treatment times, and are extremely costly. Therefore, novel therapies need to be investigated. Hydrogen sulfide (H2S), a gas produced within all mammalian cells, has been shown to play an important role in the development and progression of cancer. This study investigated the effect of inhibiting H2S production on bladder cancer progression in combination with a clinically used chemotherapy using a mouse model. Mice with bladder cancer received single and combination therapies consisting of an inhibitor of H2S production and chemotherapy. Therapies were administered directly into the mouse bladder and tumor growth was evaluated by magnetic resonance imaging and pathology. We reported that inhibition of H2S production slowed the growth of the bladder tumors and reduced their invasiveness. Moreover, we reported that inhibition of H2S production increased the anti-cancer effects of chemotherapy as a reduction in both bladder tumor size and invasiveness was observed compared to chemotherapy alone. Therefore, we conclude that inhibiting H2S production in conjunction with chemotherapy may serve as an improved combination therapy for bladder cancer.

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