Hedrich William D, Wang Hongbing
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA.
Bristol-Myers Squibb Company, Pharmaceutical Candidate Optimization, Metabolism and Pharmacokinetics, Rt. 206 and Province Line Road, Princeton, New Jersey, 08543, USA.
Pharm Res. 2021 Feb;38(2):213-241. doi: 10.1007/s11095-021-02997-y. Epub 2021 Feb 22.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that governs a highly conserved pathway central to the protection of cells against various oxidative stresses. However, the biological impact of xenobiotic intervention of Nrf2 in physiological and pathophysiological conditions remains debatable. Activation of Nrf2 in cancer cells has been shown to elevate drug resistance and increase cell survival and proliferation, while inhibition of Nrf2 sensitizes cancer cells to drug treatment. On the other hand, activation of Nrf2 in normal healthy cells has been explored as a rather successful strategy for cancer chemoprevention. Selective activation of Nrf2 in off-target cells has recently been investigated as an approach for protecting off-target tissues from untoward drug toxicity. Specifically, induction of antioxidant response element genes via Nrf2 activation in cardiac cells is being explored as a means to limit the well-documented cardiotoxicity accompanied by cancer treatment with commonly prescribed anthracycline drugs. In addition to cancers, Nrf2 has been implicated in many other diseases including Alzheimer's and Parkinson's Diseases, diabetes, and cardiovascular disease. In this review, we discuss the roles of Nrf2 and its downstream target genes in the treatment of various diseases, and its recently explored potential for increasing the benefit: risk ratio of commonly utilized cancer treatments.
核因子红细胞2相关因子2（Nrf2）是一种转录因子，它调控着一条高度保守的信号通路，该通路对于保护细胞免受各种氧化应激至关重要。然而，在生理和病理生理条件下，Nrf2的外源性干预所产生的生物学影响仍存在争议。研究表明，癌细胞中Nrf2的激活会提高耐药性，并增加细胞存活和增殖，而抑制Nrf2则会使癌细胞对药物治疗敏感。另一方面，在正常健康细胞中激活Nrf2已被探索为一种相当成功的癌症化学预防策略。最近，人们研究了在非靶细胞中选择性激活Nrf2，作为一种保护非靶组织免受不良药物毒性影响的方法。具体而言，通过激活心脏细胞中的Nrf2来诱导抗氧化反应元件基因，正被探索作为一种手段，以限制常见的蒽环类药物治疗癌症时所伴随的、已被充分证明的心脏毒性。除癌症外，Nrf2还与许多其他疾病有关，包括阿尔茨海默病和帕金森病、糖尿病以及心血管疾病。在这篇综述中，我们讨论了Nrf2及其下游靶基因在各种疾病治疗中的作用，以及最近探索的其提高常用癌症治疗的获益风险比的潜力。
