The Dietary Charred Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine Acts as Both a Tumor Initiator and Promoter in the Rat Ventral Prostate

Johns Hopkins University, Baltimore, Maryland, United States
Cancer Research (Impact Factor: 9.33). 02/2007; 67(3):1378-84. DOI: 10.1158/0008-5472.CAN-06-1336
Source: PubMed


Exposure of Fisher344 rats to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine in cooked meat, causes cancer in the rat ventral prostate, while sparing the dorsolateral and anterior lobes. Uncovering the molecular mechanisms of the lobe specificity of PhIP-induced rat prostate cancer may provide clues to the pathogenesis of human prostate cancer, which is also lobe selective. We examined the prostate and other organs for mutation frequencies using transgenic Fisher344 rats (Big Blue rats) after PhIP treatment. After PhIP treatment for as early as 4 weeks, the colon, spleen, seminal vesicles, and all lobes of the prostate had significantly elevated mutation frequencies compared with the saline-treated control group, and the differences became even greater after 8 weeks. G:C --> T:A transversions were the predominant type of mutation. After 8 weeks of treatment with PhIP, the Ki-67 index was increased (P < 0.001) in the ventral prostate, but not in the dorsolateral or anterior prostate. An increase in the number of stromal mast cells and macrophages was seen in the ventral prostate, but not in the other prostatic lobes. The apoptotic index also increased in the ventral lobe only. The increased proliferation and cell death in response to PhIP indicates that in addition to PhIP acting as an "initiator" of cancer, PhIP is also acting like an organ- and lobe-specific tumor "promoter." The prostate lobe-specific infiltration of mast cells and macrophages in response to PhIP suggests a potential new mechanism by which this dietary compound can increase cancer risk-by prompting inflammation.

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    • "Infiltration of mast cells is the sign of initiation of inflammation. Recent experiments indicate that mast cell infiltration can enhance carcinogenesis [64]–[68] and they have also long been known to drive angiogenesis and tumour growth [67]. In this study, it was observed that there is marked infiltration of mast cells in the sub-mucosal layer in DMH-treated group while there is no mast cells infiltration in control group. "
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    ABSTRACT: Colon carcinogenesis is a multistep process and it emanates from a series of molecular and histopathological alterations. Glycyrrhizic acid (GA) is a natural and major pentacyclic triterpenoid glycoside of licorice roots extracts. It has several pharmacological and biological properties such as anti-inflammatory, anti-viral, and anti-cancer. In the present study, we investigated the chemopreventive potential of GA against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions i.e., aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. Animals were divided into 5 groups. In group III, IV and V, GA was administered at the dose of 15 mg/kg b. wt. orally while in group II, III and IV, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b.wt once a week for first 5 weeks and animals were euthanized after 9 weeks. GA supplementation suppressed the development of precancerous lesions and it also reduced the infiltration of mast cells, suppressed the immunostaining of Ki-67, NF-kB-p65, COX-2, iNOS and VEGF while enhanced the immunostaining of p53, connexin-43, caspase-9 and cleaved caspase-3. GA treatment significantly attenuated the level of TNF-α and it also reduced the depletion of the mucous layer as well as attenuated the shifting of sialomucin to sulphomucin. Our findings suggest that GA has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of GA.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "Macrophages have shown clearly to aid in both the initiation and progression of experimental cancers [79]. Similar increases in mast cells and macrophages were observed in rats exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine in cooked meat at high temperatures [80]; then, the inflammatory response to PhIP may help explain the tissue-specific and prostate lobe-specific carcinogenesis in the rat prostate induced by a long term dietary carcinogen [81]. Moreover, after castration, an increase of the mast cells can be observed in the rat prostate; besides, the number of ED-1-immunostained macrophages was also markedly increased in the epithelium and in the stroma of the rat ventral prostate [82]. "
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    ABSTRACT: Carbamazepine (CBZ) is a first-line antiepileptic drug (AED), although it is also used for the treatments of psychiatric disorders and neuropathic pain. The CBZ utilization has been associated with male reproductive damage, including hormonal alterations, sexual dysfunction and reduction of sperm quality. The wide and long-term use of the CBZ is a common schedule in children and adolescents and alters the testosterone level in adult rats and humans. The objective of this work was to evaluate the CBZ side effects on the ventral prostate of rats from pre-puberty to sexual maturation, since the prostate is an androgen-dependent organ. Twenty three day-old male albino Wistar rats received CBZ diluted in propylene glycol (20 mg/Kg/i.p via). The treatment lasted 20, 40 and 70 days, according to the different stages of the rat sexual maturation. At the end of each treatment period, ventral prostates were removed and histologically processed. The prostate sections were submitted to the histopathological, morphological and stereological analyses using image analysis system. Reductions of the glandular epithelium, glandular lumen and fibromuscular stroma volume of the ventral prostate were observed in adult rats treated with CBZ since the weaning. Triggering and degranulation of mast cells were observed in the fibromuscular stroma of prepubertal and pubertal CBZ treated rats. The results suggest a direct effect of the CBZ on rat ventral prostate, evidenced by increase of mast cell and macrophage populations during pre-puberty and puberty causing a ventral prostate accentuated damage in the adult phase.
    Full-text · Article · Mar 2012 · Reproductive Biology and Endocrinology
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    • "For the first time, inflammatory-like changes could be induced in prostates of Noble rats by co-administration of testosterone and 17 beta oestradiol (Tam et al., 2007). In addition, treatment with the chemical carcinogen PhIP which is present in red meat may induce morphological changes such as chronic inflammation , proliferative inflammatory atrophy, and prostate intraepithelial neoplasia (Borowsky et al., 2006; Nakai et al., 2007). The role of pro-inflammatory cytokines in these pre-malignant lesions has not been clarified so far but may represent an interesting area of investigation in order to delineate their specific functions during early prostate tumour development. "
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    ABSTRACT: Several cytokines are involved in regulation of cellular events in prostate cancer. Interleukin-6 (IL-6) was frequently investigated in prostate cancer models because of its increased expression in cancer tissue at early stages of the disease. In patients with metastatic prostate cancer, it is well-known that IL-6 levels increase in serum. High levels of IL-6 were measured in the supernatants of cells which do not respond to androgenic stimulation. IL-6 expression in prostate cancer increases due to enhanced expression of transforming growth factor-beta, and members of the activating protein-1 complex, and loss of the retinoblastoma tumour suppressor. IL-6 activation of androgen receptor (AR) may contribute to progression of a subgroup of prostate cancers. Results obtained with two prostate cancer cell lines, LNCaP and MDA PCa 2b, indicate that IL-6 activation of AR may cause either stimulatory or inhibitory responses on proliferation. Interestingly, prolonged treatment with IL-6 led to establishment of an IL-6 autocrine loop, suppressed signal transducer and activator of transcription (STAT)3 activation, and increased mitogen-activated protein kinase phosphorylation. In several cell lines IL-6 acts as a survival molecule through activation of the signalling pathway of phosphotidylinositol 3-kinase. Expression of suppressors of cytokine signalling (SOCS) has been studied in prostate cancer. SOCS-3 prevents phosphorylation of STAT3 and is an important anti-apoptotic factor in AR-negative prostate cancer cells. Experimental therapy against IL-6 in prostate cancer is based on the use of the monoclonal antibody siltuximab which may be used for personalised therapy coming in the future.
    Full-text · Article · Jun 2011 · Molecular and Cellular Endocrinology
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