Skin and salivary gland carcinogenicity of 7,12-dimethylbenz[a]anthracene is equivalent in the presence or absence of aryl hydrocarbon receptor

Ide, Fumio; Suka, Noriyuki; Kitada, Munenori; Sakashita, Hideaki; Kusama, Kaoru; Ishikawa, Takatoshi

doi:10.1016/j.canlet.2004.04.014

Cited by 22 publications

(18 citation statements)

References 29 publications

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“…As shown in Figure 3, visnagin and khellin treatment elevated CYP1B1 gene expression, whereas MNF successfully counteracted this induction. CYP1B1 is involved in steroid breakdown [42] and of crucial relevance regarding the carcinogenicity of certain PAHs, especially 7,12-dimethylbenz(a) anthracene [43,44]. Moreover, we observed increased level of CYP1B1 protein in the presence of both furanochromones as well (Figure S1).…”

Section: Resultsmentioning

confidence: 72%

Khellin and Visnagin Differentially Modulate AHR Signaling and Downstream CYP1A Activity in Human Liver Cells

et al. 2013

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Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.

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Section: Resultsmentioning

confidence: 72%

Khellin and Visnagin Differentially Modulate AHR Signaling and Downstream CYP1A Activity in Human Liver Cells

et al. 2013

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“…The role of the AhR in other mouse models that develop cancer has not been determined and the contributions (if any) of endogenous AhR ligands are also unknown. There is evidence that the AhR plays a role in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis; however, this is most likely due to AhR-dependent induction of CYP1A/CYP1B enzymes required for metabolic activation of PAHs [40,41]. …”

Section: Role Of the Ahr In Carcinogenesismentioning

confidence: 99%

The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy

Safe

Cheng

Jin

2017

Current Opinion in Toxicology

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The aryl hydrocarbon receptor (AhR) is overexpressed in some patients with different tumor types, and the receptor can be a negative or positive prognostic factor. There is also evidence from both in vivo and in vitro cell culture models that the AhR can exhibit tumor-specific pro-oncogenic and tumor suppressor-like functions and therefore can be treated with AhR antagonists or agonists, respectively. Successful clinical applications of AhR ligands will require the synthesis and development of selective AhR modulators (SAhRMs) with tumor-specific AhR agonist or antagonist activity, and some currently available compounds such as indole-3-carbinol and diindolylmethane-(DIM) and synthetic AhR antagonists are potential drug candidates. There is also evidence that some AhR-active pharmaceuticals, including tranilast, flutamide, hydroxytamoxifen and omeprazole or their derivatives, may be effective AhR-dependent anticancer agents for single or combination cancer chemotherapies for treatment of breast and pancreatic cancers.

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“…This problem, largely reflecting our lack of understanding of the possible correlation between histological patterns and tumor prognosis, has been the focus of extensive review. 2 Several approaches, including the use of chemicals, 5 viruses, 6 radioactive isotopes, 7 and genetically engineered animals (reviewed by Dardick 8 ), have been used to developed experimental models that may help understand the carcinogenic process in salivary glands. Compared to other approaches, transgenic mouse models have the advantage of allowing a refined molecular dissection of each of the steps involved in tumor development and progression, because the variability within a given model is generally low and the carcinogenic events proceed through homogeneous steps and similar histological changes.…”

mentioning

confidence: 99%

Rapid Development of Salivary Gland Carcinomas upon Conditional Expression of K-ras Driven by the Cytokeratin 5 Promoter

Raimondi

Vitale‐Cross

Amornphimoltham

et al. 2006

The American Journal of Pathology

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We have used a recently described model in which a ras oncogene is expressed in cytokeratin 5 (K5)-expressing cells on doxycycline administration to explore the effects of this oncogene in salivary glands of adult mice. Inducible expression of a mutated K-ras gene under the control of the K5 promoter led to the development of hyperplastic and dysplastic epithelial lesions and carcinomas, with an incidence of 100% and a minimum latency of a week. All major salivary glands were affected, as well as a set of previously undescribed buccal accessory salivary glands located on the apex of the masseter muscle, close to the oral angle. The tumors appear to arise from the cytokeratin 5-positive basal cell compartment. Myoepithelial cells participated in the hyperplasias but not in carcinomas, because the tumors are negative for smooth muscle actin. Carcinomas did not accumulate immunoreactive p53 but are positive for p63, as assayed by immunohistochemistry using an antibody against the N terminus of ⌬N p63, a splice variant of p63 that can inhibit p53 transcriptional activity. In this study, we provide evidence that the ras oncogene, targeted to a specifically sensitive cell compartment within the salivary glands, can trigger a series of event that are sufficient for full carcinogenesis. (Am J Pathol

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Skin and salivary gland carcinogenicity of 7,12-dimethylbenz[a]anthracene is equivalent in the presence or absence of aryl hydrocarbon receptor

Cited by 22 publications

References 29 publications

Khellin and Visnagin Differentially Modulate AHR Signaling and Downstream CYP1A Activity in Human Liver Cells

Khellin and Visnagin Differentially Modulate AHR Signaling and Downstream CYP1A Activity in Human Liver Cells

The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy

Rapid Development of Salivary Gland Carcinomas upon Conditional Expression of K-ras Driven by the Cytokeratin 5 Promoter

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