Mondal Debasis, Narwani Devin, Notta Shahnawaz, Ghaffar Dawood, Mardhekar Nikhil, Quadri Syed S A
Debusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN 37932, USA.
Cancer Drug Resist. 2021 Mar 19;4(1):96-124. doi: 10.20517/cdr.2020.71. eCollection 2021.
Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.
雄激素剥夺疗法（ADT）是雄激素依赖性前列腺癌（PCa）患者的主要治疗方案。然而，雄激素非依赖性癌细胞的选择会导致去势抵抗性前列腺癌（CRPC）。CRPC细胞的侵袭性表型凸显了阐明抑制CRPC生长的机制和治疗策略的必要性。尽管进行了ADT，但雄激素受体（AR）转录因子通过与平行信号通路的串扰持续激活。目前尚缺乏对这些信号级联在ADT后如何启动和放大的了解。激素剥夺会增加氧化应激，由此产生的活性氧（ROS）可能会激活AR和非AR信号。此外，ROS诱导的炎性细胞因子可能会进一步放大这些氧化还原信号通路，以增强AR功能。然而，使用ROS淬灭小分子抗氧化剂的临床试验并未抑制CRPC的进展，这表明需要更有效和持续地抑制CRPC细胞中的氧化还原信号。转录因子Nrf2可增加多种抗氧化酶的表达，并下调炎性转录因子（如核因子κB）的功能。我们记录到Nrf2过表达可抑制CRPC细胞系中AR介导的转录。此外，两种Nrf2激活剂，萝卜硫素（一种植物化学物质）和巴多昔芬甲基（一种正在进行临床试验的药物）可降低AR水平，并使CRPC细胞对抗雄激素敏感。这些观察结果表明，强效Nrf2激活剂有助于抑制导致CRPC生长的致命信号级联反应。这篇综述文章将阐述在PCa进展为CRPC过程中增强AR信号的氧化还原信号网络，以及Nrf2激活剂作为ADT辅助药物的潜在用途。
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