Effects of isothiocyanates on tumorigenesis by benzo[a]pyrene in murine tumor models

Lin, Jingqiang; Amin, Shantu; Trushin, Neil; Hecht, Stephen S.

doi:10.1016/0304-3835(93)90237-4

Cited by 71 publications

(41 citation statements)

References 21 publications

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“…The A/J mouse model has been extensively used in the study of chemopreventive agents for lung tumor initiation (17,19,25). We have previously shown in A/J mice that phenethyl isothiocyanate-Nacetylcysteine given in the diet after B(a)P treatment also significantly inhibits the development of lung adenomas (18,21). However, its potential against tumor progression has not been fully explored.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, isothiocyanate conjugates can be considered prodrugs of parent isothiocyanate compounds. Isothiocyanates are versatile chemopreventive agents, because a number of isothiocyanates and their N-acetylcysteine conjugates have been shown to inhibit lung tumor development when given prior to or during carcinogen exposure (16)(17)(18)(19)(20)(21). Mechanisms of isothiocyanates as anticarcinogens of the lung cancer have been attributed to the inhibition of phase I enzymes and/or to the induction of the activity of phase II conjugation enzymes for metabolism of carcinogens (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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We have shown previously that naturally occurring isothiocyanates derived from cruciferous vegetables and their N-acetylcysteine conjugates inhibit lung adenoma formation induced by tobacco carcinogens in A/J mice at the postinitiation stage. The tumor-inhibitory activity by these compounds is linked with activation of activator protein and induction of apoptosis in lung tissues, suggesting that these compounds may also inhibit the development of adenomas to adenocarcinomas in lung. In this study, the chemopreventive activity of phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates during progression of lung adenomas to malignant tumors was investigated in A/J mice. Mice were divided into 14 groups and treated with a mixture of 3 Mmol benzo(a)pyrene [B(a)P] and 3 Mmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks. Twenty weeks after the beginning of carcinogen administration, a total of 20 mice in the treatment groups were sacrificed with an average yield of 7.3 F 4.5 lung adenomas per mouse. The remaining mice in each group were fed diets containing phenethyl isothiocyanate (3 and 1.5 mmol/kg diet), sulforaphane (3 and 1.5 mmol/kg diet), phenethyl isothiocyanate-N-acetylcysteine (8 and 4 mmol/kg diet), sulforaphane-N-acetylcysteine (8 and 4 mmol/kg diet) during weeks 21 to 42. Four mice in each of the high-dose treatment groups were sacrificed during weeks 28 and 36 and the bioassay was terminated during week 42; lung tissues were harvested for histopathologic examination of tumors and for cell proliferation (proliferating cell nuclear antigen) and apoptosis (caspase-3) assays using immunohistochemical staining. At termination, the incidence of adenocarcinoma in the 3 mmol/kg diet phenethyl isothiocyanate group and 8 mmol/kg diet phenethyl isothiocyanate-N-acetylcysteine group was reduced to 19% and 13%, respectively, compared with 42% in the carcinogen-treated control group. At the lower doses, phenethyl isothiocyanate and its N-acetylcysteine conjugate also inhibited the incidences of lung adenocarcinoma, however, the decreases were not statistically significant. The lung tumor incidences in groups treated with sulforaphane-N-acetylcysteine in the diet were also significantly reduced to 11% or 16%. Furthermore, the malignant lung tumor multiplicity was significantly reduced from 1.0 tumor/ mouse in the carcinogen-treated control group to 0.3 in the sulforaphane low-dose group, 0.3 and 0.4 in the two sulforaphane-N-acetylcysteine groups, and 0.4 in the phenethyl isothiocyanate high-dose group. The malignant tumor multiplicities in other treatment groups were also reduced (0.5-0.8 tumors/mouse), but not significantly. Unlike lung adenocarcinomas, both incidences and multiplicities of lung adenomas were not much affected by treatment with isothiocyanates or their conjugates. Immunohistochemical examination of the lung tumors from all time points indicated that significant reduction in proliferating cell nuclear antigen and induction...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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“…It has also been reported that BITC inhibits the migration and invasion of SK-Hep1 human hepatoma cells [15] and HT-29 human colon cancer cells [16]. Furthermore, BITC has been demonstrated to inhibit the hepatocarcinogenesis induced by diethylnitrosamine in rats [17], mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene in rats [18], and lung tumorigenesis induced by benzo(a)pyrene in A/J mice [19]. Recently, Warin et al [20] reported that dietary BITC prevents mammary carcinogenesis in MMTV-neu mice, a mouse model exhibiting mammary-specific expression of the neu oncogene [21].…”

Section: Introductionmentioning

confidence: 98%

Oral administration of benzyl-isothiocyanate inhibits solid tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice

Kim

Hong

Eom

et al. 2010

Breast Cancer Res Treat

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Benzyl-isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has also been shown to have anti-tumor properties. To evaluate the effects of BITC administration on the tumor growth and metastasis of breast cancer, 4T1 murine mammary carcinoma cells were injected into the inguinal mammary fat pads of syngeneic female BALB/c mice. One day later, the mice were subjected to gavage for 4 weeks with BITC (0, 5, or 10 mg/kg body weight/day). Oral BITC treatment induced a significant reduction in the growth of solid tumors. BITC reduced hemoglobin contents and CD31 and vascular endothelial growth factor (VEGF) expression in the tumors, as well as circulating levels of VEGF. Reduced expressions of proliferating cell nuclear antigen and cyclin-dependent kinase 4 were noted in the tumors of BITC-treated mice. BITC markedly increased the numbers of apoptotic cells with increased Bax expression, cleaved caspase-3, and PARP levels, but reduced Bcl-2 expression in tumor tissues. In addition, BITC was shown to reduce the numbers of pulmonary tumor nodules and the total pulmonary metastatic volume. BITC induced a significant reduction in the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and urokinase-type plasminogen activator in the sera and lungs of 4T1 cell-injected mice. However, the concentrations of TIMP-2 and plasminogen activator inhibitor-1 were increased in the sera and lungs of BITC-treated mice. The results of this study indicate that BITC has potential as a preventive agent for metastatic breast cancer.

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“…[1][2][3][4] 6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC) is found in wasabi (Wasabia japonica), a Japanese indigenous herb, and a variety of studies on the anticancer properties of 6-MITC have been described, 5,6) with 6-MITC attracting great attention as a new possible candidate for controlling cancer cell progression and metastasis. Anticancer activity of 6-MITC in vitro was studied with a human cancer cell (HCC) panel and 6-MITC directly affected the cells in the HCC panel.…”

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confidence: 99%

Detection of 6-(Methylsulfinyl)hexyl Isothiocyanate (6-MITC) and Its Conjugate with N-Acetyl-L-cysteine (NAC) by High Performance Liquid Chromatograpy-Atmospheric Pressure Chemical Ionization Mass Spectrometry (HPLC-MS/APCI)

et al. 2008

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Previous reports have documented that some isothiocyanates (ITCs) prevent the formation of cancers in animal models.1-4) 6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC) is found in wasabi (Wasabia japonica), a Japanese indigenous herb, and a variety of studies on the anticancer properties of 6-MITC have been described, 5,6) with 6-MITC attracting great attention as a new possible candidate for controlling cancer cell progression and metastasis. Anticancer activity of 6-MITC in vitro was studied with a human cancer cell (HCC) panel and 6-MITC directly affected the cells in the HCC panel.5) A suppression was found in the growth and survival of the cells in culture, and the affected cells were very specific, which included breast cancer and melanoma cell lines. A "COMPARE" analysis using a computerized algorithm, which was based on the HCC database, suggested the suppression mechanism of 6-MITC is unique, involving multiple pathways, and may be different from those of other known chemicals. Another 6-MITC-related anticancer study involves the oral administration of 6-MITC and its effects on the macroscopic pulmonary metastasis. Murine B16-BL6 melanoma cells were injected subcutaneously or intravenously in C57BL/6J mice and the effects of 6-MITC on the metastatic foci formation in the lungs were analyzed.6) The number of metastasized cells in the lungs was significantly reduced by the administration of 6-MITC, and 56% of foci formation was inhibited by the 2 week-prior administration, whereas only 27% inhibition was obtained by the concomitant administration with the cancer cell injection.Anti-cancer activities of ITCs largely involve modulation of metabolism for carcinogens through inhibition of the phase 1 enzymes and/or induction of the phase 2 enzymes, such as glutathione S-transferase and quinone reductase (QR). [7][8][9][10][11][12] In our previous study, we reported that 6-MITC induced QR activity in Hepa1c1c7 cells in a dose-dependent manner.13) However, when the dose level was high at 80 mM, the effect of 6-MITC was nullified and it significantly reduced QR activity. Augmentation of QR activity by 6-MITC seemed to be due to the increase in its mRNA expression, and the inhibition of its activity at 80 mM was ascribed to the reduced gene expression. This negative effect of 6-MITC at 80 mM was overcome by N-acetyl-L-cysteine (NAC) treatment but its mechanism is still unknown.High-performance liquid chromatography (HPLC) combined with mass spectrometry (MS) has been documented as a useful tool for detecting bioactive components, such as flavonoids, puerarin and saponins in herbal medicines, [14][15][16][17] and HPLC with an ultraviolet-ray (UV) detector and MS has been applied for determining some of these components. 18,19) Although HPLC-MS is a more expensive and complex option than other HPLC or TLC detectors, it can greatly simplify sample pre-treatment procedures and shorten separation times in HPLC due to the high selectivity and sensitivity of MS detection. 20) As mentioned earlier, the negative effect o...

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Effects of isothiocyanates on tumorigenesis by benzo[a]pyrene in murine tumor models

Cited by 71 publications

References 21 publications

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

Oral administration of benzyl-isothiocyanate inhibits solid tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice

Detection of 6-(Methylsulfinyl)hexyl Isothiocyanate (6-MITC) and Its Conjugate with N-Acetyl-L-cysteine (NAC) by High Performance Liquid Chromatograpy-Atmospheric Pressure Chemical Ionization Mass Spectrometry (HPLC-MS/APCI)

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