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A Standardized Wedelia chinensis Extract Overcomes the Feedback Activation of HER2/3 Signaling upon Androgen-Ablation in Prostate Cancer

机译:标准化的Wedelia chinensis提取物克服了前列腺癌中雄激素消融后HER2 / 3信号的反馈激活。

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摘要

Crosstalk between the androgen receptor (AR) and other signaling pathways in prostate cancer (PCa) severely affects the therapeutic outcome of hormonal therapy. Although anti-androgen therapy prolongs overall survival in PCa patients, resistance rapidly develops and is often associated with increased AR expression and upregulation of the HER2/3-AKT signaling pathway. However, single agent therapy targeting AR, HER2/3 or AKT usually fails due to the reciprocal feedback loop. Previously, we reported that wedelolactone, apigenin, and luteolin are the active compounds in Wedelia chinensis herbal extract, and act synergistically to inhibit the AR activity in PCa. Here, we further demonstrated that an herbal extract of W. chinensis (WCE) effectively disrupted the AR, HER2/3, and AKT signaling networks and therefore enhanced the therapeutic efficacy of androgen ablation in PCa. Furthermore, WCE remained effective in suppressing AR and HER2/3 signaling in an in vivo adapted castration-resistant PCa (CRPC) LNCaP cell model that was insensitive to androgen withdrawal and second-line antiandrogen, enzalutamide. This study provides preclinical evidence that the use of a defined, single plant-derived extract can augment the therapeutic efficacy of castration with significantly prolonged progression-free survival. These data also establish a solid basis for using WCE as a candidate agent in clinical studies.
机译:前列腺癌(PCa)中雄激素受体(AR)与其他信号通路之间的串扰会严重影响激素疗法的治疗效果。尽管抗雄激素疗法可延长PCa患者的总体生存期,但耐药性会迅速发展,并且通常与AR表达增加和HER2 / 3-AKT信号通路的上调有关。但是,针对AR,HER2 / 3或AKT的单药治疗通常会因相互反馈回路而失败。以前,我们曾报道维德内酯,芹菜素和木犀草素是中草药Wedelia chinensis提取物中的活性化合物,并起协同作用抑制PCa中的AR活性。在这里,我们进一步证明了中华草药提取物(WCE)有效地破坏了AR,HER2 / 3和AKT信号网络,因此增强了PCa中雄激素消融的疗效。此外,在体内适应去势抵抗性PCa(CRPC)LNCaP细胞模型中,WCE仍然有效抑制AR和HER2 / 3信号传导,该模型对雄激素戒断和二线抗雄激素enzalutamide不敏感。这项研究提供了临床前证据,即使用确定的单一植物来源提取物可以提高去势治疗的疗效,并显着延长无进展生存期。这些数据也为在临床研究中使用WCE作为候选药物奠定了坚实的基础。

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