Department of Chemistry, Roger Adams Laboratory, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
ACS Chem Biol. 2013 Oct 18;8(10):2173-83. doi: 10.1021/cb4005832. Epub 2013 Aug 22.
A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a challenging task, as it requires identifying a cellular component that is altered in cancer, but not normal cells, and discovering a compound that specifically interacts with it. The enzyme NQO1 is a potential target for personalized medicine, as it is overexpressed in many solid tumors. In normal cells NQO1 is inducibly expressed, and its major role is to detoxify quinones via bioreduction; however, certain quinones become more toxic after reduction by NQO1, and these compounds have potential as selective anticancer agents. Several quinones of this type have been reported, including mitomycin C, RH1, EO9, streptonigrin, β-lapachone, and deoxynyboquinone (DNQ). However, no unified picture has emerged from these studies, and the key question regarding the relationship between NQO1 processing and anticancer activity remains unanswered. Here, we directly compare these quinones as substrates for NQO1 in vitro, and for their ability to kill cancer cells in culture in an NQO1-dependent manner. We show that DNQ is a superior NQO1 substrate, and we use computationally guided design to create DNQ analogues that have a spectrum of activities with NQO1. Assessment of these compounds definitively establishes a strong relationship between in vitro NQO1 processing and induction of cancer cell death and suggests these compounds are outstanding candidates for selective anticancer therapy.
肿瘤个性化医学的主要目标是根据癌细胞的特定特征识别具有可预测疗效的药物，这已经在格列卫（Bcr-Abl 蛋白的存在）、赫赛汀（Her2 过表达）和易瑞沙（存在特定的 EGFR 突变）中得到证实。这是一项具有挑战性的任务，因为它需要识别在癌细胞中改变但在正常细胞中不变的细胞成分，并发现与该成分特异性相互作用的化合物。NQO1 酶是个性化医学的一个潜在靶点，因为它在许多实体瘤中过度表达。在正常细胞中，NQO1 是可诱导表达的，其主要作用是通过生物还原使醌类解毒；然而，某些醌类在被 NQO1 还原后变得更具毒性，这些化合物具有作为选择性抗癌剂的潜力。已经报道了几种此类醌类化合物，包括丝裂霉素 C、RH1、EO9、streptonigrin、β-拉帕醌和脱氧新醌（DNQ）。然而，这些研究没有形成统一的认识，关于 NQO1 处理与抗癌活性之间的关系的关键问题仍然没有答案。在这里，我们直接比较这些醌类化合物作为 NQO1 的体外底物，以及它们以 NQO1 依赖的方式在培养的癌细胞中杀死癌细胞的能力。我们表明，DNQ 是一种优越的 NQO1 底物，我们使用计算指导设计来创建具有 NQO1 活性谱的 DNQ 类似物。这些化合物的评估明确确立了体外 NQO1 处理与诱导癌细胞死亡之间的强相关性，并表明这些化合物是选择性抗癌治疗的优秀候选物。
