Urothelial carcinoma is one of the most common urinary cancers, with tumor recurrence and metastasis being major prognostic factors. In 2023, an estimated 168,560 cases of urinary cancer will be diagnosed in the United States, with approximately 32,590 deaths; approximately 50% of these cases are urothelial carcinoma. Despite the availability of new treatment options, such as platinum-based chemotherapy and PD1 antibody-based immunotherapy, more than half of urothelial carcinoma patients still do not respond to these treatments. Therefore, there is an urgent need to investigate new therapeutic agents to improve the prognosis of urothelial carcinoma patients.
Icariin (ICA), the main active ingredient in Epimedium, is a tonic, aphrodisiac, and anti-rheumatic traditional Chinese medicine. Once ingested, ICA is metabolized to icartin (ICT), which then exerts its effects. ICA has multiple biological activities, including regulating adaptive immunity, having antioxidant properties, and inhibiting tumor progression. In 2022, Icaritin capsules with ICT as the main ingredient were approved by the China National Medical Products Administration (NMPA) for the first-line treatment of advanced inoperable hepatocellular carcinoma. In addition, it showed significant efficacy in prolonging the overall survival of patients with advanced hepatocellular carcinoma. ICT not only directly kills tumors by inducing apoptosis and autophagy, but also regulates the tumor immune microenvironment and promotes anti-tumor immune response. However, the specific mechanism by which ICT regulates TME, especially in urothelial carcinoma, is not fully understood.
Recently, researchers from the Department of Urology, Huashan Hospital, Fudan University published an article entitled "Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation" in the journal Acta Pharm Sin B. The study revealed that icariin significantly reduced tumor spread and progression while inhibiting neutrophil infiltration and NET synthesis, indicating that ICT may be a new NETs inhibitor and a new treatment for urothelial carcinoma.
Tumor recurrence and metastasis are the main causes of death in urothelial carcinoma. In the tumor microenvironment, negative regulatory molecules and multiple immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, there are currently no drugs that specifically inhibit neutrophils and NETs.
In this study, the researchers demonstrated for the first time that icariin, a first-line treatment for advanced and incurable hepatocellular carcinoma, can reduce NETs caused by suicidal NETosis and prevent neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby inhibiting PADI2-mediated histone citrullination. In addition, ICT inhibits ROS generation, inhibits the MAPK signaling pathway, and suppresses NET-induced tumor metastasis.
At the same time, ICT inhibits tumor PADI2-mediated histone citrullination, thereby inhibiting the transcription of neutrophil recruitment genes such as GM-CSF and IL-6. In turn, downregulation of IL-6 expression forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, the researchers found a correlation between neutrophils, NETs, UCa prognosis and immune escape. ICT combined with immune checkpoint inhibitors may have a synergistic effect.
In summary, this study found that icariin significantly reduced tumor spread and progression while inhibiting neutrophil infiltration and NET synthesis, and neutrophils and NETs played an inhibitory role in the tumor immune microenvironment of patients with urothelial carcinoma. In addition, ICT combined with anti-PD1 immunotherapy has a synergistic effect, suggesting a potential treatment strategy for patients with urothelial carcinoma
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Post time: Nov-14-2024
