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Published on: July 28, 2012
Pharmacological Inhibition of Endogenous Hydrogen Sulfide Production Slows Bladder Cancer Progression in an
Sydney Relouw1,2, George J Dugbartey2,3,4,5, Patrick McLeod2
1Department of Microbiology & Immunology, Western University, London, ON N6A 5C1, Canada.
Abstract:
Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.
Insights
Inhibiting hydrogen sulfide (H₂S) production with propargylglycine reduced bladder cancer cell viability and tumor growth. This approach enhanced gemcitabine chemotherapy, offering a potential new treatment strategy for bladder cancer.
Area of Science:
- Urology
- Oncology
- Biochemistry
Background:
- Current bladder cancer therapies have limited efficacy and high costs.
- There is a critical need for novel and improved bladder cancer treatment strategies.
- Endogenous hydrogen sulfide (H₂S) production's role in bladder cancer requires further investigation.
Purpose of the Study:
- To investigate the effects of inhibiting endogenous H₂S production on bladder cancer cell viability and tumor progression.
- To evaluate propargylglycine, an H₂S inhibitor, alone and in combination with gemcitabine in a murine bladder cancer model.
Main Methods:
- In vitro studies using 5637 bladder cancer cells treated with propargylglycine.
- In vivo studies utilizing an intravesical murine bladder cancer model.
- Assessment of cell viability, tumor growth, invasion, apoptosis, immune cell infiltration, and neovascularization via magnetic resonance imaging and immunohistochemistry.
Main Results:
- Propargylglycine significantly reduced bladder cancer cell viability in vitro and inhibited tumor growth and invasion in vivo.
- Combination therapy with propargylglycine and gemcitabine led to significant tumor regression.
- Propargylglycine promoted apoptosis, increased CD8+ T cell and macrophage infiltration, reduced neovascularization, and decreased cell proliferation.
Conclusions:
- Inhibition of endogenous H₂S production via propargylglycine demonstrates significant anti-cancer effects in bladder cancer.
- Propargylglycine potentiates the efficacy of gemcitabine chemotherapy, suggesting a synergistic therapeutic approach.
- Targeting H₂S production represents a promising novel strategy for future bladder cancer diagnosis and treatment.
