Revealing that traditional Chinese medicine Acoradine may become a new therapy for drug-resistant prostate cancer

The internationally renowned oncology journal "Carcinogenesis" (IF 5.266) recently published an article titled "A New Method for Prostate Cancer Treatment: Acoradine activates aromatic hydrocarbon receptors to target androgen receptors and their variants" (original link: http://carcin.oxfordjournals.org/content/early/2015/04/21/carcin.bgv040.abstract?sid=8547563c -e40d-4393-9bad-f60322e9070c ）， This study was conducted by Professor Eu Leung Yong's research group at the National University of Singapore School of Medicine.
Prostate cancer is a hormone stimulated disease and is a high-risk cancer in male patients. Due to the large number of patients, prostate cancer drugs have always been a hot area of drug development. At present, prostate cancer that is sensitive to androgens can be effectively controlled by drugs, but there is still a significant unmet clinical need for prostate cancer patients who are insensitive to androgens. The sustained activation of the androgen receptor (AR) signaling pathway is an important factor in the development of androgen insensitive prostate cancer, with the C-terminal deletion variant isoforms (ARvs) of AR playing a crucial role. A series of drugs such as Enzalutamide and Abiraterone have been developed based on AR targets, but over 30% of prostate cancer patients quickly develop resistance. Further research has found that their resistance is highly correlated with the main variant isomer AR-v7 in ARvs, and there are currently no effective drugs targeting AR-v7 in clinical practice. Therefore, developing drugs targeting AR-v7 has become an international drug development hotspot. Aromatic hydrocarbon receptor (AhR) is a cytoplasmic transcription factor that plays an important role in regulating autoimmunity and tumor immunity. Preclinical studies and tumor patient tissue studies have shown that the binding of tryptophan (TRP) metabolite kynurenine (KYN) to AhR affects the redifferentiation selection of Na? Ve CD4+Th cells, making them more inclined to differentiate into Treg cell subsets rather than Th17 cell subsets capable of producing cytokine IL-17.
Professor Yong's research group has discovered for the first time that Acoradine, a natural isopentene flavonoid compound, can target AR and AR-v7. Akoladine promotes the ubiquitination degradation of AR and AR-v7 by binding to AhR. In both androgen sensitive and insensitive prostate cancer mouse models, Acoradine exhibited inhibitory effects on the AR signaling pathway and tumor growth, without significant toxicity. This article suggests that Acoradine may become a novel drug molecule for the treatment of AR positive prostate cancer.
Akoladine is a national first-class original new drug for traditional Chinese medicine/natural medicine developed by Beijing Shenaoji Pharmaceutical Company. It has completely independent intellectual property rights and has received support from the national "Twelfth Five Year Plan" major new drug creation project, as well as investment from multiple venture capital companies such as IDG, Junlian Capital, Qiming Capital, Lida Capital, etc. At present, Acoradine is about to complete phase II clinical trials and has achieved the expected goals. Due to the breakthrough progress in the mechanism of action and biomarker research of the drug, it will submit a new drug certificate application to the National Medical Products Administration in June 2015 as a breakthrough therapy.
English abstract:
Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide and enzalutamide, which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin, can co-target both persistent AR and ARvs. Icaritin was found to inhibit transcription of key AR regulated genes, such as KLK3 (PSA) and ARvs regulated genes,  such as UBE2C and induce apoptosis in AR-positive prostate cancer cells. Mechanistically, icaritin promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, icaritin impaired AR transactivation in prostate cancer cells. Knockdown of AhR gene restored AR stability and partially prevented icaritin-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and castration-resistant prostate cancer cells, icaritin was able to target AR and ARvs, to inhibit AR signaling, and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of icaritin,  as a novel lead compound for AR-positive prostate cancer therapeutics, especially for those bearing AR splice variants.