Carcinogenicity of 1-Hydroxy-3-methylcholanthrene and Its Electrophilic Sulfate Ester 1-Sulfooxy-3-methylcholanthrene in Sprague-Dawley Rats

Flesher, James W.; Horn, Jamie; Lehner, Andreas F.

doi:10.1006/bbrc.1997.8048

Cited by 23 publications

(14 citation statements)

References 24 publications

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“…In contrast, treatment of Spalax led to necrotic wounds, which completely healed with no signs of malignancy. The carcinogen 3-MCA is known to produce fibrosarcomas through persistent inflammation and reactive metabolites causing severe oxidative damage [27]. In our study, 100% of 3-MCA-injected mice and rats developed tumors at the injection site within two to three and four to six months, respectively.…”

Section: Discussionsupporting

confidence: 47%

Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitroevidence

Manov

Hirsh

Iancu³

et al. 2013

BMC Biol

105

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BackgroundSubterranean blind mole rats (Spalax) are hypoxia tolerant (down to 3% O2), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years of Spalax research, spontaneous tumors have never been recorded among thousands of individuals. Here we addressed the questions of (1) whether Spalax is resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated from Spalax possess tumor-suppressive activity.ResultsTreating animals with 3-Methylcholantrene (3MCA) and 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmed Spalax high resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, among Spalax no tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2 Spalax individuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment. In vitro experiments showed an extraordinary ability of normal Spalax cultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolated Spalax 3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction with Spalax fibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar to Spalax, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat or Acomys. Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells.ConclusionsThis report provides pioneering evidence that Spalax is not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability of Spalax normal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowing Spalax to survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans.

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Section: Discussionsupporting

confidence: 47%

Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitroevidence

Manov

Hirsh

Iancu³

et al. 2013

BMC Biol

105

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“…Activation of p53 occurs in response to a number of cellular stresses, including DNA damage, and leads to the activation of several genes whose product trigger cell cycle arrest, apoptosis, or DNA repair (44). Several PAH metabolites possess high mutagenic activity that can induce p53 through their DNA-damaging activity (41,42). B(a)P treatment of murine 3T3 cells has been shown to result in DNA damage associated with elevated levels of nuclear p53 (45).…”

Section: Discussionmentioning

confidence: 99%

“…Treatment of a cell with the AhR ligands TCDD, 3-MC, and B(a)P activates transcription of the genes coding for DME regulated by the AhR⅐Arnt complex. Upon metabolic activation, genotoxic metabolites of 3-MC and B(a)P are generated (3-MC* and B(a)P*) that can cause DNA damage, such as 1-sulfooxy-3-MC and B(a)P-7,8-diol-9,10-epoxide, that can form DNA adducts and thus act as mutagens (42,52). TCDD, the prototypical AhR ligand, is resistant to metabolic breakdown and is nongenotoxic.…”

Section: Discussionmentioning

confidence: 99%

“…p53-mediated Induction of the mdr1 Promoter by Xenobiotic Compounds-Several metabolites of 3-MC possess high mutagenic activity (41,42) and thus could induce p53 through their DNA-damaging activity. To test this hypothesis, we have investigated the effect of three additional xenobiotic compounds with different genotoxic activities on p53 activation and mdr1 transcriptional induction: (i) B(a)P, a PAH and AhR ligand that, like 3-MC, is not in itself genotoxic but that is oxidized to reactive species by AhR⅐Arnt-regulated DME (12); (ii) TCDD, another AhR ligand that is nongenotoxic and resistant to metabolic breakdown (12); and (iii) DN, an anticancer drug and potent genotoxic agent that was recently shown to induce rat mdr1b expression via p53 (36).…”

Section: Transcriptional Induction Of the Mouse Mdr1 Gene By 3-mcmentioning

confidence: 99%

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Aromatic Hydrocarbon Receptor (AhR)·AhR Nuclear Translocator- and p53-mediated Induction of the Murine Multidrug Resistance mdr1 Gene by 3-Methylcholanthrene and Benzo(a)pyrene in Hepatoma Cells

Mathieu

Lapierre

Brault

et al. 2001

Journal of Biological Chemistry

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The mouse multidrug resistance gene family consists of three genes (mdr1, mdr2, and mdr3) encoding P-glycoprotein. We show that the expression of mdr1 is increased at the transcriptional level upon treatment of the hepatoma cell line Hepa-1c1c7 with the polycyclic aromatic hydrocarbon 3-methylcholanthrene (3-MC). This increase is not observed in the aromatic hydrocarbon receptor (AhR)-defective TAOc1BP r c1 and the AhR nuclear translocator (Arnt)-defective BP r c1 variants, demonstrating that the induction of mdr1 by 3-MC requires AhR⅐Arnt. We show that the mdr1 promoter (؊1165 to ؉84) is able to activate the expression of a reporter gene in response to 3-MC in Hepa-1c1c7 but not in BP r c1 cells. Deletion analysis indicated that the region from ؊245 to ؊141 contains cis-acting sequences mediating the induction, including a potential p53 binding sequence. 3-MC treatment of the cells increased the levels of p53 and induced p53 binding to the mdr1 promoter in an AhR⅐Arnt-dependent manner. Mutations in the p53 binding site abrogated induction of mdr1 by 3-MC, indicating that p53 binding to the mdr1 promoter is essential for the induction. Benzo(a)pyrene, a polycyclic aromatic hydrocarbon and AhR ligand, which, like 3-MC, is oxidized by metabolizing enzymes regulated by AhR⅐Arnt, also activated p53 and induced mdr1 transcription. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, an AhR ligand resistant to metabolic breakdown, had no effect. These results indicate that the transcriptional induction of mdr1 by 3-MC and benzo(a)pyrene is directly mediated by p53 but that the metabolic activation of these compounds into reactive species is necessary to trigger p53 activation. The ability of the anticancer drug and potent genotoxic agent daunorubicin to induce mdr1 independently of AhR⅐Arnt further supports the proposition that mdr1 is transcriptionally up-regulated by p53 in response to DNA damage.

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“…Resulting metabolites react with the 2-amino group of guanine to produce bulky carcinogen-DNA adducts, which are associated with G⅐C 3 T⅐A transversions (3). MCA is also hydroxylated at the C1 position to form a major oxidation product, 1-hydroxy-3-methylchloranthrene (4). Esterification of this metabolite produces 1-sulfooxy-3-methylchloranthrene, which generates a highly reactive carbonium ion capable of damaging the nucleotide base structure (4), thus introducing mutagenic and carcinogenic properties into DNA (5).…”

mentioning

confidence: 99%

Development of a cancer DNA phenotype prior to tumor formation

Malins

Anderson

Gilman

et al. 2004

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

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Using the carcinogen 3-methylcholanthrene (MCA), we demonstrate with Fourier transform-infrared spectroscopy that a cancer DNA phenotype is produced well in advance of palpable tumors. We further demonstrate that the administration of cyclophosphamide markedly inhibits the development of the cancer phenotype and concomitantly delays tumor formation. MCA, injected into the hind legs of mice, produced a variety of significant structural changes in the nucleotide bases and phosphodiester-deoxyribose backbone, as reflected in a substantial (34%) difference between the mean DNA spectra of the control and the MCA-injected mice. Strikingly, 57 days before the mean appearance of tumors, we could not distinguish the DNA structure of the histologically normal tissues of the MCA-injected mice from the DNA structure of the tumor tissues. This finding indicates the early development of a cancer phenotype. Confirmatory evidence was obtained when tissues from a group of mice injected with both MCA and cyclophosphamide did not manifest the cancer phenotype, and their mean DNA structure closely resembled that of the control mice. Accordingly, we propose that the cancer DNA phenotype, as evinced by Fourier transform-infrared spectroscopy, is a promising early indicator of tumor formation, and we postulate that agents capable of inhibiting this phenotype may delay or prevent carcinogenesis.3-methylcholanthrene ͉ antineoplastic agents ͉ cyclophosphamide ͉ cancer inhibition ͉ cancer prediction

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Carcinogenicity of 1-Hydroxy-3-methylcholanthrene and Its Electrophilic Sulfate Ester 1-Sulfooxy-3-methylcholanthrene in Sprague-Dawley Rats

Cited by 23 publications

References 24 publications

Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitroevidence

Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitroevidence

Aromatic Hydrocarbon Receptor (AhR)·AhR Nuclear Translocator- and p53-mediated Induction of the Murine Multidrug Resistance mdr1 Gene by 3-Methylcholanthrene and Benzo(a)pyrene in Hepatoma Cells

Development of a cancer DNA phenotype prior to tumor formation

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