Targeting cancer cachexia via inhibition of soluble epoxide hydrolase
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Citation
Abstract
Cancer cachexia is an incapacitating condition characterized by progressive muscle wasting and hyperinflammation, for which there are currently no effective therapeutic remedies available. The underlying mechanisms of cachexia remain poorly understood. However, studies now understand the involvement of a storm of pro-inflammatory cytokines and immune cell infiltration, resulting in apoptotic cell death (debris) and systemic inflammation. Understanding the involvement of the immune system and the ability to ameliorate this hyperinflammatory response may lead to further advancements in the treatment of cachexia. Inflammation resolution is an active biological process stimulated and regulated by specialized pro-resolving lipid mediators (SPMs), such as arachidonic acid-derived epoxyeicosatrienoic acids (EETs). However, EETs are rapidly metabolized by the enzyme soluble epoxide hydrolase (sEH), which exacerbates inflammation and is a biomarker in various chronic inflammatory diseases. We propose that inhibition of sEH will promote tissue regeneration and counteract the pro-inflammatory cytokine storm, making it a potential treatment target for reversing and preventing cachexia. To investigate this hypothesis, murine cancer cachexia models were utilized, including genetically engineered pancreatic (KPCY) mice, transgenic murine prostate adenocarcinoma (TRAMP) mice, and colon cancer cell lines (CT26) that we injected into C57BL6/J mice. After sacrificing the mouse models and tissue collection, we performed LC-MS/MS-based profiling of bioactive lipids using the plasma from KPCY and CT26-colon cancer cachectic mice, revealing a pro-inflammatory eicosanoid-driven cytokine storm induced by cancer cachexia. KPCY cells injected intraperitoneally (IP) induced 19.7% and 54.1% reduction in muscle weight in the tibialis anterior and soleus, respectively, in immunocompetent C57BL/6 mice compared to non-tumor bearing (NTB) mice. Treatment with the human sEH inhibitor, EC5026, delayed the onset of cachexia and significantly improved survival rates in both KPCY and TRAMP models. A survival of over 250 days was observed post-injection in the KPCY model (n = 15 mice/group). In the TRAMP model, 5/5 of mice treated with EC5026 survived 230 days post-treatment compared to no survival of vehicle-treated mice (n = 5 mice/group). Initially, sEH expression was upregulated in the gastrocnemius of KPCY mice by day 22 after tumor cell injection compared to NTB mice. However, treatment with EC5026 reversed this increase in sEH expression observed in the muscles of KPCY mice. The transplantation of KPCY resulted in reduced levels of CD8+ T lymphocytes and NK cells, with a significant increase in macrophages in all organs (brain, liver, spleen, heart, and skeletal muscles) of mice compared to those without tumors, as assessed by flow cytometry analysis. Administration of EC5026 led to an increase in CD8+ T lymphocytes and NK cells while attenuating the macrophage infiltration and eicosanoid-driven cytokine storm. Treatment with EC5026 resulted in higher organ weights (brain, liver, spleen, heart, and skeletal muscles) and an overall increase in body weights compared to KPCY cachexic mice treated with the vehicle. The inhibition of sEH could serve as a novel therapeutic target to stimulate the resolution of inflammation without causing toxicity or immunosuppression, consequently resolving the overactive immune response and cachexia. Given the safety and efficacy of sEH inhibitors demonstrated in clinical trials for controlling various inflammatory diseases, this research provides a promising foundation for the clinical translation of sEH inhibitors to prevent or reverse cachexia in cancer patients. This study provides a starting block to understanding vital immune cell populations, cytokines, and their relative population changes between healthy and disease in cancer cachexia. T and B lymphocyte, macrophage, NK, and PMN (neutrophil) populations seem crucial in the progression of this debilitating disease. Understanding the role these cells play in cancer, especially when paired with immune-checkpoint blockades or chemotherapy treatment remedies, will be critical in not just resolving cachexia but also reducing tumor burden and morbidity.
Description
2024