The role of dual COX-2/sEH inhibitors in bladder cancer
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Citation
Abstract
The immune system can be thought of as a double-edged sword, the smallest teetering of the scale can take us from our cells seeking out to protect us by eliminating a mutated cell or harm us by causing an allergic reaction. It has long been known that the immune system can detect and kill cancerous cells by detecting cancerous antigens. However, the cells of the immune system can cause inflammation due to the release of cytokines, and those cytokines can further potentiate further cytokine release. Chronic inflammation is a mechanistic process linked to multiple disease, but here we will focus on how inflammation can become detrimental in cancer treatment and prognosis. More specifically, the role that the inhibition of the enzymes, cyclooxygenase-2 (COX- 2) and soluble epoxide hydrolase (sEH) may play in cancer. We will focus on the anti-tumorigenic role of a dual eicosanoid pathway modulating inhibitor of COX-2 and sEH (PTUPB) in bladder cancer initiation and progression in murine models. Chemotherapy has been the standard of care for bladder cancer. However, chemotherapy can induce tumor-promoting inflammation. We hypothesized that PTUPB can counter-regulate sEH and COX-2 expression inimmunocompetent mice. When the murine bladder tumors (MB49) reached ~200 mm3 the mice were treated with PTUPB, chemotherapy, immunotherapy, or a combination of each. The monotherapy groups did suppress tumor growth compared to the untreated control group, however, the tumors escaped monotherapy by the end of the study. Dual COX-2/sEH inhibition in combination with chemotherapy or immunotherapy resulted in sustained tumor regression. The use of PTUPB also prolonged survival in an orthotopic MB49 bladder tumor model. The result of this demonstrated that dual eicosanoid pathway (COX-2/sEH) inhibition can be a novel approach to enhance immunotherapy in bladder cancer.
Description
2024