Abstract
Contemporary therapy for advanced castration-resistant prostate cancer (CRPC) employs reagents such as enzalutamide and abiraterone acetate targeting the androgen receptor (AR) transcription axis only provide a temporary response and rapidly develop resistance. Additionally, neuroendocrine prostate cancer (NEPC) is an AR pathway-independent and lethal-stage prostate cancer with no standard therapy. Qingdai Decoction (QDT), a traditional Chinese medicine formula, has various pharmacological activities and was widely used for the treatment of different diseases including prostatitis which may contribute to prostate cancer development. This study aims to explore the anti-tumor role and potential mechanism of QDT on prostate cancer. CRPC prostate cancer cell models and xenograft mice models were established for research. The effect of TCMs on cancer growth and metastasis were determined by CCK-8, wound-healing assays and the PC3-xenografted mice model. The toxicity of QDT in the major organs was investigated by H&E staining. The compound-target network was analyzed with network pharmacology. The correlation of QDT targets with prostate cancer patient's prognosis was analyzed with multiple prostate cancer patient cohorts. The expression of related proteins and mRNA were detected by western blot and real-time PCR. The gene knockdown was achieved with CRISPR-Cas13 technology. By integrating functional screening, network pharmacology analysis, CRISPR-Cas13 directed RNA targeting, and molecular biology validation in different prostate cancer models and clinical prostate cancer cohorts, we found that Qingdai Decoction (QDT), a Traditional Chinese Medicine, can repress cancer growth in advanced prostate cancer models in vitro and in vivo in an AR independent manner by targeting NOS3, TGFB1, and NCOA2. This study not only identified QDT as a novel drug for lethal-stage prostate cancer treatment but also provided an extensive Integrative research paradigm for investigating the roles and mechanisms of TCMs for the treatment of other diseases.
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