Investigations on organ-specific metabolism and genotoxic effects of the urinary bladder carcinogen N-nitrosobutyl-3-carboxypropylamine (BCPN) and its analogs N-nitrosodibutylamine (NDBA) and N-nitrosobutyl-4-hydroxybutylamine (4-OH-NDBA)

Janzowski, C.; Jacob, D.; Henn, Indiara Welter; Zankl, Heinrich; Poole-Zobel, B.L.; Eisenbrand, Gerhard

doi:10.1016/0300-483x(89)90057-7

Cited by 15 publications

(11 citation statements)

References 33 publications

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“…Damaged cells are known to release danger-associated molecular patterns as well as pattern-associated molecular patterns which initiate and potentiate noninfectious and infectious inflammatory response which is in line with the expression of proinflammatory cytokines, chemokines and TLRs that we observe already at the 2 weeks of BBN treatment, similar to findings previously described in different cancer models [24]. Gradual downregulation of the inflammatory response during the exposure to BBN might be a consequence of urothelial adaptation via upregulation of metabolic pathways that manage oxidative damage and DNA repair coupled to increased urothelial proliferation [25]. In support of this, we observed an upregulation of IL4, a pro-resolving mediator of inflammation, which was one of the most prominently expressed cytokines at 2 weeks of BBN treatment.…”

Section: Discussionsupporting

confidence: 85%

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

et al. 2019

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BackgroundBladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC.MethodsBladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment.ResultsWe characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape.ConclusionsDespite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

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Section: Discussionsupporting

confidence: 85%

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

et al. 2019

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“…After treatment with BBN, GSTM1 mRNA expression didn’t change in T24 cells ( S3 Fig ). It indicates that BBN treatment in vitro maybe different from in vivo because liver metabolism is deficient in cell culture [ 25 ]. In order to determine whether the human GSTM1 gene is silenced by DNA methylation or not, T24 cells were chose and then treated with a DNA methyltransferase inhibitor 5-aza-dC to investigate the GSTM1 expression.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression and DNA Methylation Status of Glutathione S-Transferase Mu1 and Mu5 in Urothelial Carcinoma

et al. 2016

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Bladder cancer is highly recurrent after therapy, which has an enormous impact on the health and financial condition of the patient. It is worth developing diagnostic tools for bladder cancer. In our previous study, we found that the bladder carcinogen BBN increased urothelial global DNA CpG methylation and decreased GSTM1 protein expression in mice. Here, the correlation of BBN-decreased GSTM1 and GSTM gene CpG methylation status was analyzed in mice bladders. BBN treatment decreased the protein and mRNA expression of GSTM1, and the CpG methylation ratio of GSTM1 gene promoter was slightly increased in mice bladders. Unlike mouse GSTM1, the human GSTM1 gene tends to be deleted in bladder cancers. Among 7 human bladder cancer cell lines, GSTM1 gene is really null in 6 cell lines except one, T24 cells. The CpG methylation level of GSTM1 was 9.9% and 5-aza-dC did not significantly increase GSTM1 protein and mRNA expression in T24 cells; however, the GSTM5 gene was CpG hypermethylated (65.4%) and 5-aza-dC also did not affect the methylation ratio and mRNA expression. However, in other cell lines without GSTM1, 5-aza-dC increased GSTM5 expression and decreased its CpG DNA methylation ratio from 84.6% to 61.5% in 5637, and from 97.4% to 75% in J82 cells. In summary, two biomarkers of bladder tumor were provided. One is the GSTM1 gene which is down-regulated in mice bladder carcinogenesis and is usually deleted in human urothelial carcinoma, while the other is the GSTM5 gene, which is inactivated by DNA CpG methylation.

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“…The DNA alkylation seemed to be a butylation resulting from a-hydroxylation of the 3-carboxypropyl group and the lesion was concerned with the mutagenic eŠect. In studies using rat liver and pig urinary bladder microsomes, Janzowski et al showed that BCPN was preferentially oxidized at the a-position of the alkyl chain bearing the carboxyl group rather than the butyl chain (25). Airoldi et al also demonstrated that O 6 -butylguanine from BBN in rat urothelial and hepatic cells was detected (26,27).…”

Section: Discussionmentioning

confidence: 99%

Oxidation of N-Alkyl-N-(3-carboxypropyl)nitrosamines by Iron Porphyrin and Oxidant Forms Alkylating Mutagens

Inami

Yasui

Tsugumi

et al. 2013

Genes and Environment

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N-Alkyl-N-(3-carboxypropyl)nitrosamines are known to selectively induce urinary bladder tumor in rats and mice. To detect DNA damage by N-alkyl-N-(3-carboxypropyl)nitrosamines, we evaluated their mutagenicity using the Ames assay in S. typhimurium and E. coli under oxidative conditions of chemical model for cytochrome P450. The activation system consisted of 5,10,15,20-tetrakis(1methylpyridinium-4-yl)porphyrinatoiron(III) pentachloride (4-MPy) plus an oxidant. The N-alkyl-N-(3-carboxypropyl)nitrosamines; N-methyl-N-(3-carboxypropyl)nitrosamine (MCPN), N-ethyl-N-(3-carboxypropyl)nitrosamine (ECPN), N-propyl-N-(3-carboxypropyl)nitrosamine (PCPN), N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), were treated with 4-MPy and t-BuOOH in acetonitrile for 30 min at room temperature, the reaction mixture was extracted with dichloromethane, and the organic phase was assayed for their mutagenicity in Salmonella typhimurium TA1535 and Escherichia coli WP2 uvrA. The dichloromethane extract derived from the reaction mixture of MCPN, ECPN, PCPN or BCPN with 4-MPy plus t-BuOOH was mutagenic in both of the strains, indicating that N-alkyl-N-(3-carboxypropyl)nitrosamines were oxidized to direct-acting mutagens by the 4-MPy plus t-BuOOH. The mutagenicity of oxidized BCPN extract in S. typhimurium YG7108 was higher than that in S. typhimurium TA1535, suggesting that the mutagenicity derived from BCPN was due to DNA alkylation. Furthermore, the DNA seemed to be butylated, not 3-carboxypropylated, exerting the mutagenicity of BCPN in the presence of 4-MPy and t-BuOOH.

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Investigations on organ-specific metabolism and genotoxic effects of the urinary bladder carcinogen N-nitrosobutyl-3-carboxypropylamine (BCPN) and its analogs N-nitrosodibutylamine (NDBA) and N-nitrosobutyl-4-hydroxybutylamine (4-OH-NDBA)

Cited by 15 publications

References 33 publications

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

Gene Expression and DNA Methylation Status of Glutathione S-Transferase Mu1 and Mu5 in Urothelial Carcinoma

Oxidation of N-Alkyl-N-(3-carboxypropyl)nitrosamines by Iron Porphyrin and Oxidant Forms Alkylating Mutagens

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