Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA.
Biochem Pharmacol. 2012 Apr 15;83(8):1033-40. doi: 10.1016/j.bcp.2011.12.017. Epub 2011 Dec 24.
Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical trials. For many quinones reduction to the hydroquinone has been shown to play a key role in their antitumor activity. The two-electron reduction of quinones by NQO1 has been shown to be an efficient pathway to hydroquinone formation. NQO1 is expressed at high levels in many human solid tumors making this enzyme ideally suited for intracellular drug activation. Cellular levels of NQO1 are influenced by the NQO12 polymorphism. Individuals homozygous for the NQO12 allele are NQO1 null and homozygous NQO122 cell lines have been shown to be more resistant to antitumor quinones when compared to isogenic cell lines overexpressing NQO1. In this review we will discuss the role of NQO1 in the sensitivity and resistance of human cancers to the quinone antitumor drugs mitomycin C, β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors including 17-AAG. The role of NQO1 in the bioreductive activation of mitomycin C remains controversial but pre-clinical data strongly suggests a role for NQO1 in the activation of β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors. Despite a large volume of preclinical data demonstrating that NQO1 is an important determinant of sensitivity to these antitumor quinones there is little information on whether the clinical response to these agents is influenced by the NQO12 polymorphism. The availability of simple assays for the determination of the NQO12 polymorphism should facilitate clinical testing of this hypothesis.
醌类化合物是一类庞大而多样的抗肿瘤药物，许多醌类化合物已被批准用于临床应用，或正在临床试验中进行评估。对于许多醌类化合物，还原为对苯二酚已被证明在其抗肿瘤活性中起着关键作用。NQO1 将醌类化合物还原为二氢醌已被证明是形成对苯二酚的有效途径。NQO1 在许多人类实体瘤中高表达，使该酶非常适合细胞内药物激活。NQO1 的细胞水平受 NQO12 多态性的影响。NQO12 等位基因纯合的个体是 NQO1 无效的，并且已证明 NQO122 细胞系与过表达 NQO1 的同源细胞系相比，对抗肿瘤醌类药物更具抗性。在这篇综述中，我们将讨论 NQO1 在人类癌症对米托蒽醌、β-拉帕醌和苯醌类 HSP90 抑制剂（包括 17-AAG）等醌类抗肿瘤药物的敏感性和耐药性中的作用。NQO1 在米托蒽醌的生物还原激活中的作用仍存在争议，但临床前数据强烈表明 NQO1 在β-拉帕醌和苯醌类 HSP90 抑制剂的激活中起作用。尽管有大量的临床前数据表明 NQO1 是这些抗肿瘤醌类化合物敏感性的重要决定因素，但关于这些药物的临床反应是否受 NQO12 多态性的影响的信息很少。用于确定 NQO12 多态性的简单测定方法的可用性应有助于对此假设进行临床测试。
