Department of Medicine Division of Hematology/Oncology University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, USA.
Molecules. 2019 Aug 28;24(17):3121. doi: 10.3390/molecules24173121.
Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus.
急性髓系白血病（AML）是一种肿瘤性疾病，源于未分化的幼稚髓系细胞的克隆性增殖。明确的遗传和表观遗传异常是 AML 的关键特征，导致其对标准治疗的反应各不相同。无论其致癌突变如何，AML 细胞都会产生高水平的活性氧（ROS）。它们还改变抗氧化酶的表达和活性，以促进细胞增殖和存活。随后，在 AML 等分子异质性疾病中选择性靶向氧化还原平衡已成为开发新型抗白血病化疗药物的一种有吸引力的方法。萘醌能够在癌细胞中进行氧化还原循环并产生 ROS，这使它们成为对抗 AML 细胞的优秀候选物。除了在 AML 细胞中诱导氧化失衡外，萘醌衍生物还根据其结构对其他细胞装置产生负面影响，导致肿瘤细胞死亡。在这里，我们概述了萘醌衍生物的抗 AML 活性，并分析了它们的作用机制，包括诱导氧化还原失衡、改变线粒体跨膜电位、Bcl-2 调节、引发 DNA 损伤以及调节 MAPK 和 STAT3 活性、未折叠蛋白反应的改变以及 FOX 相关转录因子向核内易位。
