Suppression of 7,12-Dimethylbenz(α) Anthracene-Induced Breast Carcinoma by Coumarin in the Rat

Feuer, G.; Kellen, J; Kovacs, K

doi:10.1159/000225098

Cited by 82 publications

(33 citation statements)

References 16 publications

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“…The vitamin K-deficient animals were restored to a normal diet 2 mo before tumors could be identified. Similarly a reduction in 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats pretreated with coumarin was also reported by Feuer et al (34).…”

Section: Discussionsupporting

confidence: 79%

Vitamin K as a regulator of benzo(a)pyrene metabolism, mutagenesis, and carcinogenesis. Studies with rat microsomes and tumorigenesis in mice.

Israels¹,

Walls²,

Ollmann³

et al. 1983

J. Clin. Invest.

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A B S T R A C T Vitamin K3 inhibits the conversion of benzo(a)pyrene to its more polar metabolites in an in vitro rat liver microsomal system. Vitamin K3 also inhibits benzo(a)pyrene metabolism in rat liver fragments and reduces its mutagenicity in the Ames test. Higher concentrations of vitamin K3 are required to comparably reduce benzo(a)pyrene metabolism when the microsomal system has been induced with 3-methylcholanthrene. High pressure liquid chromatography analysis of the products of benzo(a)pyrene metabolism shows a uniform reduction of all the metabolic products. When tumors were induced in ICR/Ha female mice by the intraperitoneal injection of benzo(a)pyrene, those mice given vitamin K3 before or both before and after benzo(a)pyrene had a slower rate of tumor appearance and tumor death rate as compared with those receiving benzo(a)pyrene alone. However, vitamin K, increased the rate of tumor death while vitamin K deprivation and warfarin decreased the rate of tumor appearance and death in benzo(a)pyrene-injected mice.These studies indicate that vitamin K3 is an inhibitor of aryl hydrocarbon hydroxylase and reduces the carcinogenic and mutagenic metabolites in vitro, and inhibits benzo(a)pyrene tumorigenesis in vivo. That vitamin K, enhances the benzo(a)pyrene effect while warfarin and vitamin K deficiency inhibit benzo(a)pyrene tumorigenesis indicates that vitamin K1, vitamin K deprivation, or possibly blockade of its metabolic cycle also modulates benzo(a)pyrene metabolism in vivo but by a mechanism or at a site different from the vitamin K3 effect. The vitamin K series should be considered as capable of serving a regulatory func-

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Section: Discussionsupporting

confidence: 79%

Vitamin K as a regulator of benzo(a)pyrene metabolism, mutagenesis, and carcinogenesis. Studies with rat microsomes and tumorigenesis in mice.

Israels¹,

Walls²,

Ollmann³

et al. 1983

J. Clin. Invest.

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confidence: 99%

Mitochondrial Production of Reactive Oxygen Species Mediate Dicumarol-induced Cytotoxicity in Cancer Cells

Daniels

Asbury

et al. 2006

Journal of Biological Chemistry

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(1,(5)(6)(7)(8). Dicumarol-induced cytotoxicity is not from interference with vitamin K epoxide oxidoreductase or a previously unrecognized aspect of vitamin K metabolism, since the addition of vitamin K does not impair the growth inhibiting effect of dicumarol. The growth inhibitory effect of dicumarol may also be relatively specific for tumor cells, since proliferation of normal human airway myocytes is not affected (9). Although such coumarin compounds as dicumarol have been utilized in cancer therapy, little is known about the mechanism of action of these drugs. NADPH:quinone oxidoreductase (NQO1) is responsible for the two-electron reduction of quinones using NADPH or NADH as an electron donor (10). Dicumarol inhibits NQO1 resulting in increased oxidative stress within the cell, leading to increased cell toxicity (11,12).Recent studies have demonstrated that dicumarol causes cytotoxicity against human pancreatic cancer cells that have overexpression and increased activity of NQO1 (13). Dicumarol increased intracellular levels of superoxide (O 2 . ), as measured by hydroethidine staining, and inhibited cell growth. Both of these effects (cell growth inhibition and hydroethidine staining) were blunted with infection of an adenoviral vector containing the cDNA for manganese superoxide dismutase (Mn-SOD), 2 a mitochondrial antioxidant enzyme that scavenges O 2. . This study compliments the recent study from Li et al. (14) that similar compounds as dicumarol result in increased mitochondrial O 2 . production leading to apoptosis, whereas others have demonstrated that dicumarol acts intracellularly to uncouple mitochondrial oxidative phosphorylation at the NADH-cytochrome b5 site (15). These studies suggest that mitochondrial metabolism might be involved in the process that caused cytotoxicity with dicumarol treatment even though the majority of NQO1 is found in the cytoplasm (16,17). Metabolic oxidative stress results from an imbalance between prooxidants (i.e. superoxide, hydrogen peroxide, etc.) produced as byproducts of oxidative metabolism and the cellular antioxidants that eliminate these species. Studies to determine whether oxidative stress from mitochondrial metabolism * This work was supported by National Institutes of Health Grants CA115785, CA100045, CA66081, and HL07485-24, the Susan L. Bader Pancreatic Cancer Research Fund, and the Medical Research Service, Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

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“…Coumarin (Table 1, Compound 1) is a widely distributed, naturally occurring flavoring agent. It protects against hydrocarbon-mediated carcinogenesis and elevates GSTs in rodent tissues (11)(12)(13)(14). We reported that coumarin raised the QR levels in Hepa lclc7 cells grown on 75-cm2 plates (CD = 100 ,uM; ref.…”

mentioning

confidence: 99%

Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis.

Talalay

Long

Prochaska

1988

Proc. Natl. Acad. Sci. U.S.A.

518

325

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Carcinogenesis is blocked by an extraordi- Although bifunctional inducers appear to elevate phase II enzymes in part by binding to the Ah (aryl hydrocarbon) receptor, the molecular mechanisms by which monofunctional inducers act are less clear (3). This paper extends our earlier efforts to identify structural features important for phase II enzyme induction by diphenols and phenylenediamines (5). Since the specific activity of QR in the Hepa lclc7 murine hepatoma cells is raised by virtually all compounds that produce coordinate elevations of phase II enzymes in vivo (4, 5, 7), this system was used to determine the potency of various types of enzyme inducers. Some inducers identified in cell culture were also tested as inducers of QR and GST in mouse tissues.We report here that phase II enzyme inducers contain, or acquire by metabolism, a hitherto unrecognized and distinctive chemical and structural feature-i.e., an electrophilic olefin or related electron-deficient center. They are, therefore, Michael reaction acceptors.t This generalization has led to the identification of a number of phase II enzyme inducers that are Michael acceptors and are potential chemoprotectors. Most inducers are also substrates for GST, but whether this merely reflects their electrophilic nature or is an intrinsic aspect of the mechanism of induction is unclear.MATERIALS AND METHODS QR activities of Hepa lclc7 murine hepatoma cells were measured in cells grown in microtiter plates (8). The potency of compounds was determined from plots relating the ratio of treated to basal (vehicle only) of specific activities of QR to the concentration of inducer. Potencies are expressed as the concentrations required to double (designated CD) the basal specific activity of QR. Induction of cytosolic QR and GST activities in female CD1 mouse tissues was assessed by a standard protocol (9, 10). All compounds were of the highest quality obtainable commercially and were purified when necessary.Abbreviations: QR, quinone reductase; GSH, glutathione; GST, glutathione S-transferase; CD, concentration of a compound that doubles the specific activity of QR; BHA, 2(3)-tert-butyl-4-hydroxyanisole; CDNB, 1-chloro-2,4-dinitrobenzene; DCNB, 1,2-dichloro4nitrobenzene. *Enzymes of xenobiotic metabolism are of two types: (i) phase I enzymes (e.g., cytochromes P450) functionalize compounds usually by oxidation or reduction; and (ii) phase II enzymes conjugate functionalized compounds with endogenous ligands (e.g., glutathione, glucuronic acid). Quinone reductase may be considered a phase II enzyme since it does not introduce new functional groups, is often induced coordinately with other phase II enzymes, and protects cells against toxic agents. tIn 1887 A. Michael reported that olefins conjugated with electronwithdrawing groups (Z) are susceptible to attack by nucleophiles. These so-called "Michael acceptors" have the structures CH2=CH-Z, Z'-CH=CH-Z (including quinones), or R-CLC-Z (acetylenes). The or4er of reactivity of CH2=CH-Z with morpholine or pyrroli...

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Suppression of 7,12-Dimethylbenz(α) Anthracene-Induced Breast Carcinoma by Coumarin in the Rat

Cited by 82 publications

References 16 publications

Vitamin K as a regulator of benzo(a)pyrene metabolism, mutagenesis, and carcinogenesis. Studies with rat microsomes and tumorigenesis in mice.

Vitamin K as a regulator of benzo(a)pyrene metabolism, mutagenesis, and carcinogenesis. Studies with rat microsomes and tumorigenesis in mice.

Mitochondrial Production of Reactive Oxygen Species Mediate Dicumarol-induced Cytotoxicity in Cancer Cells

Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis.

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