State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
Cell Rep Med. 2022 May 17;3(5):100608. doi: 10.1016/j.xcrm.2022.100608. Epub 2022 Apr 20.
Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3βHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3βHSD1, overcomes drug resistance. 3βHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3βHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3βHSD1 and suppresses prostate cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3βHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3βHSD1 inhibitor even after abiraterone and enzalutamide resistance.
需要新的策略来治疗前列腺癌，以克服对阿比特龙和恩扎鲁胺的耐药性。在这里，我们表明，阿比特龙和恩扎鲁胺治疗后增加 3βHSD1 是耐药的关键，而生物黄酮 A（BCA）作为 3βHSD1 的抑制剂，可克服耐药性。在长期接受恩扎鲁胺或阿比特龙治疗后，细胞系、活检样本和患者中的 3βHSD1 活性增加。由 3βHSD1 介导的增强的类固醇生成足以损害恩扎鲁胺的功能。在患者中，阿比特龙代谢的加速导致随着疾病的进展，血浆中的阿比特龙下降。BCA 抑制 3βHSD1，并单独或与阿比特龙和恩扎鲁胺一起抑制前列腺癌的发展。大豆黄酮，一种源自饮食的 BCA 类似物，与较高的血浆阿比特龙浓度相关，并可预防阿比特龙耐药患者的 PSA 升高。总的来说，我们的结果表明，3βHSD1 是克服耐药性的一个有前途的靶点，BCA 作为 3βHSD1 抑制剂，即使在阿比特龙和恩扎鲁胺耐药后，也能抑制疾病的进展。
