Suppression of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with β-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland

Malejka-Giganti, Danuta; Bennett, Kristen K.; Culp, Sandra J.; Beland, Frederick A.; Shinozuka, Hisashi; Bliss, Robin

doi:10.1016/j.cdp.2005.01.005

Cited by 9 publications

(6 citation statements)

References 36 publications

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“…The profound efficacy of the Ah receptor agonist is in line with prior studies showing that indole-3-carbinol (another mixed Phase I/II inducer) was similarly effective in reducing mammary tumorigenesis [33]. In fact, the results confirm efficacy studies by Malejka-Gilanti and coworkers [34]. This high efficacy may be mediated in part by the metabolism of DMBA to less carcinogenic products via specific CYP proteins.…”

Section: Discussionsupporting

confidence: 85%

Induced expression of drug metabolizing enzymes by preventive agents: Role of the antioxidant response element

Lubet

Yao²,

Grubbs

et al. 2009

Chemico-Biological Interactions

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Identifying agents that block tumor initiation is a goal of cancer prevention. The ability of a chemically varied group of agents to induce various drug metabolizing genes in livers of rats was examined. Sprague-Dawley rats were treated for seven days with various agents in the diet or by gavage. The agents examined, which might be expected to respond via specific nuclear receptors (CAR, AhR) as well as antioxidant response elements (AREs), included Phase I/II inducers [5,6 benzoflavone (BF, 5000 mg/kg diet), diallyl sulfide (DAS, 500 mg/kg BW/day), ethoxyquin (EXO, 300 mg/kg BW/day) and phenobarbital (PB, 500 mg/kg diet)] or pure Phase II inducers [1,2 dithiol-3-thione (DTT, 500 mg/kg diet), and cyclopentadithiolthione (CPDTT, 175 mg/kg BW/day)]. Liver RNA expression was analyzed employing oligonucleotide microarrays. The agents yielded unique expression profiles. In genes with known AREs, the induction ratios (Levels Treated/Levels Controls) were: Quinone Oxidoreductase (BF, 8:1; DTT, 3.2:1; CPDTT, 3:1; DAS, 1.8:1; Exo, 1.7:1), Glutatione Transferase Pi (DTT, 36:1; CPDTT 34:1; EXO, 8:1; DAS, 5:1; BF, 2.5:1), and aldehyde keto reductase 7A3 (AFAR) (DTT and CPDTT, 14:1; DAS 6:1; EXO 4:1; PB, 1.5:1). When the search included a wider variety of Phase II drug metabolizing enzymes, no clear pattern was observed. Agent induced gene expression and preventive activity in published carcinogen induced tumor models showed limited correlation; questioning whether measuring the induction of one or two genes (e.g., quinone reductase) is a surrogate for overall Phase II inducing (antioxidant) and potential anti-tumor activity.

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Section: Discussionsupporting

confidence: 85%

Induced expression of drug metabolizing enzymes by preventive agents: Role of the antioxidant response element

Lubet

Yao²,

Grubbs

et al. 2009

Chemico-Biological Interactions

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“…The solid tumor developed after 90 days. After 13 weeks, the breast tumor-bearing rats were treated for 20 days [54], [70], [71].…”

Section: Methodsmentioning

confidence: 99%

“…The blocks were cut to obtain 5 µm thick sections and stained with hemotoxylin-eosin (H & E) for histological examination [71]. Serial paraffin sections of each tissue image were captured by light microscopy (Olympus BX51, Philadelphia, USA).…”

Section: Methodsmentioning

confidence: 99%

Identification of a Novel Calotropis procera Protein That Can Suppress Tumor Growth in Breast Cancer through the Suppression of NF-κB Pathway

Samy

Rajendran

et al. 2012

PLoS ONE

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Breast cancer is the most common cancer among women. To date, improvements in hormonal and cytotoxic therapies have not yet led to a sustained remission or cure. In the present study, we investigated the in vitro and in vivo antitumor activities of a novel Calotropis procera protein (CP-P) isolated from root bark. CP-P protein inhibited the proliferation and induced apoptosis of breast cancer cells through the suppression of nuclear factor kappaB (NF-kB) activation. CP-P, when administered individually or in combination with cyclophosphamide (CYC, 0.2 mg/kg) to rats with 7, 12-dimethyl benz(a)anthracene (DMBA)-induced breast cancer decreased tumor volume significantly without affecting the body weight. To elucidate the anticancer mechanism of CP-P, antioxidant activities such as superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and non-enzymatic antioxidant - reduced glutathione (GSH), vitamin E and C generation in the breast were analyzed by various assays. SOD, CAT, GST, GSH, vitamin E and C levels were high in combination-treated groups (CP-P+CYC) versus the CYC alone-treated groups. Also, the combination was more effective in down-regulating the expression of NF-kB-regulated gene products (cyclin D1 and Bcl-2) in breast tumor tissues. Our findings indicate that CP-P possesses significant antitumor activity comparable to a commonly used anticancer drug, cyclophosphamide, and may form the basis of a novel therapy for breast cancer.

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“…On the other hand, E 2 metabolism by CYP1A (1A1 and 1A2) and CYP3A4 are true detoxification pathways forming 2-hydroxy E 2 (2-E 2 ) metabolite (anti-carcinogenic) and 16α-hydroxy E 2 metabolite, respectively (29). Since previous studies showed that modulation of hepatic xenobiotic-metabolizing enzymes affects tumor initiation and tumor incidence (26, 30), we extracted hepatic microsomes and analyzed their CYP1B1, CYP1A (1A1 and 1A2) and CYP3A4 activities (Fig 4A, B and C). …”

Section: Resultsmentioning

confidence: 99%

Curcumin Implants, Not Curcumin Diet, Inhibit Estrogen-Induced Mammary Carcinogenesis in ACI Rats

Bansal

Kausar

Vadhanam

et al. 2014

Cancer Prevention Research

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Curcumin is widely known for its anti-oxidant, anti-inflammatory and anti-proliferative activities in cell culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvents oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female ACI rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2-cm; 200 mg each; 20% drug load) 4 days prior to grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Implants were changed after 4½ months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2±1 vs 5±3; p=0.001) and tumor volume (184±198 mm3 vs 280±141 mm3; p=0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in presence of E2. Since CYP1A and 3A4 metabolize most of the E2 to its non-carcinogenic 2-OH metabolite and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by HPLC showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered.

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Suppression of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with β-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland

Cited by 9 publications

References 36 publications

Induced expression of drug metabolizing enzymes by preventive agents: Role of the antioxidant response element

Induced expression of drug metabolizing enzymes by preventive agents: Role of the antioxidant response element

Identification of a Novel Calotropis procera Protein That Can Suppress Tumor Growth in Breast Cancer through the Suppression of NF-κB Pathway

Curcumin Implants, Not Curcumin Diet, Inhibit Estrogen-Induced Mammary Carcinogenesis in ACI Rats

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