Abstract:
Introduction: Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to androgen deprivation therapy. Resistance in CRPC is often driven by AR variants and glucocorticoid receptor (GR). Thus, drugs that target both could be vital in overcoming resistance. Methods: Utilizing the STAR Drug Discovery Platform, three hundred medicinal plant extracts were examined across 25 signaling pathways to identify potential drug candidates. Effects of the botanical drug YIV-818-A, derived from optimized water extracts of Rubia cordifolia (R.C.), on Dihydrotestosterone (DHT) or Dexamethasone (DEX) induced luciferase activity were assessed in 22RV1 cells harboring the ARE luciferase reporter. Furthermore, the key active compounds in YIV-818-A were identified through activity guided purification. The inhibitory effects of YIV-818-A, RA-V, and RA-VII on AR and GR activities, their impact on AR target genes, and their roles in modifying epigenetic status were investigated. Finally, the synergistic effects of these compounds with established CRPC drugs were evaluated both in vitro and in vivo. Results: YIV-818-A was found to effectively inhibit DHT or DEX induced luciferase activity in 22RV1 cells. Deoxybouvardin (RA-V) was identified as the key active compound responsible for inhibiting AR and GR activities. Both YIV-818-A and RA-V, along with RA-VII, effectively downregulated AR and AR-V proteins through inhibiting protein synthesis, impacted the expression of AR target genes, and modified the epigenetic status by reducing levels of Bromodomain and Extra-Terminal proteins (Brd2/Brd4) and H3K27Ac. Furthermore, these compounds exhibited synergistic effects with apalutamide, darolutamide, or enzalutamide, and suppressed AR mediated luciferase activity of 22RV1 cells. Co-administration of YIV-818-A and enzalutamide led to a significant reduction of 22RV1 tumor growth in vivo. Different sources of R.C. had variable levels of RA-V, correlating with their potency in AR inhibition. Discussion: YIV-818-A, RA-V, and RA-VII show considerable promise in addressing drug resistance in CRPC by targeting both AR protein and GR function, along with modulation of vital epigenetic markers. Given the established safety profile of YIV-818-A, these findings suggest its potential as a chemopreventive agent and a robust anti-prostate cancer drug.
摘要:
简介:前列腺癌是美国男性癌症死亡的第二大原因。去势抵抗性前列腺癌(CRPC)通常对雄激素剥夺疗法产生抗性。CRPC中的抗性通常由AR变体和糖皮质激素受体(GR)驱动。因此,针对两者的药物在克服耐药性方面可能至关重要。方法:利用STAR药物发现平台,在25个信号通路中检查了300种药用植物提取物,以鉴定潜在的候选药物。植物药YIV-818-A的作用,从优化的茜草(R.C.)水提取物中提取,在含有ARE荧光素酶报道分子的22RV1细胞中评估双氢睾酮(DHT)或地塞米松(DEX)诱导的荧光素酶活性。此外,YIV-818-A中的关键活性化合物通过活性指导纯化鉴定。YIV-818-A的抑制作用,RA-V,和RA-VII关于AR和GR活动,它们对AR靶基因的影响,并研究了它们在改变表观遗传状态中的作用。最后,在体外和体内评估了这些化合物与已建立的CRPC药物的协同作用。结果:YIV-818-A能有效抑制DHT或DEX诱导的22RV1细胞荧光素酶活性。脱氧布瓦丁(RA-V)被鉴定为负责抑制AR和GR活性的关键活性化合物。YIV-818-A和RA-V,还有RA-VII,通过抑制蛋白质合成有效下调AR和AR-V蛋白,影响AR靶基因的表达,并通过降低溴结构域和外端蛋白(Brd2/Brd4)和H3K27Ac的水平来修饰表观遗传状态。此外,这些化合物与阿帕鲁胺表现出协同作用,达鲁柳胺,或者恩扎鲁他胺,并抑制了AR介导的22RV1细胞的荧光素酶活性。YIV-818-A和恩杂鲁胺的共同给药导致体内22RV1肿瘤生长的显着降低。不同来源的R.C.有不同水平的RA-V,与它们在AR抑制中的效力相关。讨论:YIV-818-A,RA-V,RA-VII在通过靶向AR蛋白和GR功能解决CRPC中的耐药性方面显示出相当大的希望,以及重要的表观遗传标记的调节。鉴于YIV-818-A的既定安全性,这些发现表明其作为化学预防剂和强大的抗前列腺癌药物的潜力。