NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones

Siegel, David; Yan, Chao; Ross, David

doi:10.1016/j.bcp.2011.12.017

Cited by 240 publications

(260 citation statements)

References 91 publications

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Section: Introductionmentioning

confidence: 99%

“…The mechanism of its antitumor effect is considered to involve the formation of reactive oxygen species (ROS) (13)(14)(15). ROS and other types of radicals are involved in a variety of biological phenomena, including tumorigenesis, degenerative disease and aging (16,17), and are also important mediators of tumor cell death (18).…”

Section: Introductionmentioning

confidence: 99%

“…NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the reduction of β-lap to an unstable hydroquinone, which then undergoes rapid oxidization and is reconverted to a stable quinone (14). This repeated oxidation-reduction cycle induces ROS, partially contributing to the tumor killing activity of β-lap (14,15,18).Under physiological conditions, the intracellular level of ROS is tightly regulated by NF-E2 related factor 2 (NFE2L2, also known as NRF2) and its inhibitor protein, Kelch-like ECH-associated protein 1 (KEAP1), which mediates NRF2 degradation. NRF2 is a transcription factor that forms a heterodimer with one of the small Maf-family proteins and binds to an antioxidant-responsive element to activate transcription of target genes, including NQO1 (19,20).…”

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confidence: 99%

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Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

et al. 2017

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Abstract. NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as β-lapachone (β-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and β-lap has been elucidated, the effects of a NQO1-inducer and β-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17-demethoxygeldanamycin. The present study was conducted to investigate the involvement of NQO1 in β-lap-mediated toxicity and the utility of combination treatment with a NQO1-inducer and β-lap in malignant melanoma cell lines. Decreased expression or inhibition of NQO1 caused these cell lines to become less sensitive to β-lap, indicating a requirement of NQO1 activity for β-lap-mediated toxicity. Of note was that carnosic acid (CA), a compound extracted from rosemary, was able to induce further expression of NQO1 through NF-E2 related factor 2 (NRF2) stabilization, thus significantly enhancing the cytotoxicity of β-lap in all of the melanoma cell lines tested. Taken together, the data presented in the current study indicated that the NRF2-NQO1 axis may have potential value as a therapeutic target in malignant melanoma to improve the rate of clinical response to NQO1-dependent antitumor drugs. IntroductionMalignant melanoma is one of the most aggressive forms of cancer, exhibiting resistance to various forms of chemotherapy.The global incidence and mortality rates of malignant melanoma are increasing (1-3). Novel targeted therapies designed to kill melanoma cells harboring mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF) have been developed using vemurafenib, which is a specific BRAF inhibitor (4,5). Missense mutations to the BRAF gene, most commonly a valine-to-glutamic acid substitution at codon 600, has been observed in ~80% of melanocytic nevi and ~50% of melanomas (6-9). In addition to this BRAF mutation, another therapeutic target has been investigated, as melanomas, including acral lentiginous melanoma, the most common type in ethnicities that produce high levels of melanin, have a low frequency of BRAF gene mutation (10,11). However, details of the mechanism responsible for the drug insensitivity of melanomas lacking BRAF mutations have been largely unclear. On the basis of the aforementioned background, a search for novel therapeutic strategies is justified.β-lapachone (β-lap), a lipophilic cytotoxic o-naphtoquinone derived from the bark of the South American Lapacho tree (Tabebuia avellanedae), has recently attracted attention as an antitumor drug (12,13). The mechanism of its antitumor effect is considered to involve the formation of reactive oxygen species (ROS) (13-15). ROS and other types of radicals are involved in a variety of biological phenomena, including tumorigenesis, degenerative disease and aging (16,17), and are also important medi...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

et al. 2017

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“…NQO1은 세포 속에서 형성된 활성산소(reactive oxygen species)를 제거해주는 항산화제 역할을 하는 것으로 도 알려져 있다 [22,23]. NQO1은 다른 기질에 작용하여 해독 또는 독성을 야기하는 양면적인 성격을 가지고 있음도 확인되 었으며 특히 암 치료를 위한 표적 단백질로도 제시되었다 [21].…”

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“…예를 들어, NQO1에 의해 생성되는 친수성 hydroquinone의 경우 세포 밖으로 배출되기 때문에 세포 독성을 야기하지 않 는 것으로 알려져 있지만 NQO1이 조절하는 대사를 통해 강한 세포 독성을 나타내는 물질로 바뀌기도 한다고 보고되었다 [21]. 이러한 물질들은 DNA의 알킬화를 야기하거나 반응성이 높은 활성산소종의 발생을 야기하여 세포독성을 초래함으로 써 항암효과를 나타낸다고 밝혀졌다.…”

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Inhibition of NAD(P)H:Quinone Oxidoreductase 1 by Dicumarol Reduces Tight Junction in Human Colonic Epithelial Cells

Hong¹,

Zhang²,

Yoon³

et al. 2016

Journal of Life Science

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We previously showed that NAD(P)H:quinone oxidoreductase 1 (NQO1) knockout (KO) mice exhibited spontaneous inflammation with markedly increased mucosal permeability in the gut, and that NQO1 is functionally associated with regulating tight junctions in the mucosal epithelial cells that govern the mucosal barrier. Here, we confirm the role of NQO1 in the formation of tight junctions by human colonic epithelial cells (HT29). We treated HT29 cells with a chemical inhibitor of NQO1 (dicumarol; 10 μM), and examined the effect on the transepithelial resistance of epithelial cells and the protein expression levels of ZO1 and occludin (two known regulators of tight junctions between gut epithelial cells). The dicumarol-induced inhibition of NQO1 markedly reduced transepithelial resistance (a measure of tight junctions) and decreased the levels of the tested tight junction proteins. In vivo, luminal injection of dicumarol significantly increased mucosal permeability and decreased ZO1 and occludin protein expression levels in mouse guts. However, in contrast to the previous report that the epithelial cells of NQO1 KO mice showed marked down-regulations of the transcripts encoding ZO1 and occludin, these transcript levels were not affected in dicumarol-treated HT29 cells. This result suggests that the NQO1-depedent regulation of tight junction molecules may involve multiple processes, including both transcriptional regulation and protein degradation processes such as those governed by the ubiquitination/proteasomal, and/or lysosomal systems.

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Natural Products as Cytotoxic Agents

Pullman,

León,

Cutler

2021

Burger's Medicinal Chemistry and Drug Discovery

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Nature has proved to be a wellspring of important antineoplastic agents. In recent years, there has been a resurgence in the study of natural products with an emphasis on the discovery of novel therapeutic agents. New technologies and approaches such as high‐throughput screening, parallel synthesis, and other programs has facilitated this increased interest in natural products research. The scientific literature indicates that natural sources not previously considered as bioactive have in fact, become potential valuable treasure troves of novel chemical structures. For example, marine products from diverse sources such as thermal vents, sponges, terrestrial thermal vents, glacial cryogenic organisms, and xerophytic and endophytic organisms now give rise to a vast assortment of microorganisms. Additionally, the study of the biosynthetic machineries and biochemical process in microorganism has enhanced the research of cryptic natural products, fueling the search for natural products in the treatment of cancer. It comes as no surprise that nature biosynthesizes chemical compounds that chemists have not considered even in their imaginations. Although this article provides a few of these examples, it is certain that more will be present in the literature as the intellectual property in these discoveries are protected.

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NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones

Cited by 240 publications

References 91 publications

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

Inhibition of NAD(P)H:Quinone Oxidoreductase 1 by Dicumarol Reduces Tight Junction in Human Colonic Epithelial Cells

Natural Products as Cytotoxic Agents

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