Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy

Jamieson, David; Cresti, Nicola; Bray, Johanne; Sludden, Julieann; Griffin, Melanie; Hawsawi, Nahed M.; Famie, Eve; Mould, Emily; Verrill, M.; May, Felicity E. B.; Boddy, Alan V.

doi:10.1097/fpc.0b013e32834b6918

Cited by 33 publications

(26 citation statements)

References 32 publications

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“…A polymorphism of NQO1 has reportedly been associated with response to chemotherapy (47,48). Therefore the existing data indicated that confirmation of genetic background prior to β-lap treatment would be warranted for patients with malignant melanoma.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…This simple genetic test may be a more practical measure of the influence of NQO1 on quinone drug activation since this test would identify NQO1-null individuals. Complicating the association between the NQO1*2 polymorphism and response to chemotherapy are studies in women with breast cancer that have demonstrated an association of the NQO1*2 polymorphism with decreased survival in patents receiving anthracycline therapy [116, 117], however, in these studies the role of NQO1 in survival is believed to be linked to its role in p53 stabilization and or modulation of TNF-alpha and not through drug activation [116]. …”

Section: Nqo1 In the Clinicmentioning

confidence: 99%

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

Siegel

Yan

Ross

2012

Biochemical Pharmacology

238

250

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The quinone pharmacophore is present in many drug classes but is particularly common among antitumor drugs. Many quinones serve essentially as pro-drugs and exert their activities after reduction. Reduction of quinones may generate semiquinones or hydroquinones with subsequent generation of reactive oxygen radicals and oxidative stress, quinones can be designed so they lose a leaving group when reduced to the hydroquinone generating a reactive electrophile or the hydroquinone form of the molecule may have greater pharmacological activity than the parent quinone against a particular target. Enzyme systems that reduce quinones therefore become critically important in the pharmacological activity of this class of drugs. There are a number of enzyme systems that can catalyze reduction of quinones including cytochrome P450 reductase, cytochrome b5 reductase, NAD(P)H:quinone oxidoreductase 1 (NQO1), NAD(P)H:quinone oxidoreductase 2 (NQO2), carbonyl reductases, and thioredoxin reductase. In this context, one of the most extensively studied reductases has been NAD(P)H:quinone oxidoreductase 1 (NQO1). In this review we will focus on the role of NQO1 in the bioactivation of clinically important quinones mitomycin C, β-lapachone and 17AAG as well as the influence of the NQO1*2 polymorphism on the sensitivity and resistance to these agents.

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“…It also binds 60 to the tumour suppressor protein p73 and the polyamine biosynthesis 61 pathway enzyme ornithine decarboxylase [17,18]. NQO1 interacts 62 with the 20S proteasome reducing its activity, preventing it from 63 degrading these proteins; however, partially unfolded forms of NQO1 64 can be efficiently degraded by the 20S proteasome [19]. showing the location of Arg139 and Pro187.…”

Section: Nad(p)hmentioning

confidence: 99%

FAD binding overcomes defects in activity and stability displayed by cancer-associated variants of human NQO1

Pey

Megarity

Timson

2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

134

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NAD(P)H quinone oxidoreductase 1 is involved in antioxidant defence and protection from cancer, stabilizing the apoptosis regulator p53 towards degradation. Here, we studied the enzymological, biochemical and biophysical properties of two cancer-associated variants (p.R139W and p.P187S). Both variants (especially p.187S) have lower thermal stability and greater susceptibility to proteolysis compared to the wild-type. p.P187S also has reduced activity due to a lower binding affinity for the FAD cofactor as assessed by activity measurements and direct titrations. Native gel electrophoresis and dynamic light scattering also suggest that p.P187S has a higher tendency to populate unfolded states under native conditions. Detailed thermal stability studies showed that all variants irreversibly denature causing dimer dissociation, while addition of FAD restores the stability of the polymorphic forms to wild-type levels. The kinetic destabilization induced by polymorphisms as well as the kinetic protection exerted by FAD was confirmed by measuring denaturation kinetics at temperatures close to physiological. Our data suggest that the main molecular mechanisms associated with these cancer-related variants are their low binding affinity for FAD and/or kinetic instability. Thus, pharmacological chaperones may be useful in the treatment of patients bearing these polymorphisms.

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Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy

Abstract: This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.

Cited by 33 publications

References 32 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

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

FAD binding overcomes defects in activity and stability displayed by cancer-associated variants of human NQO1

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