This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, Y.-M. Articles by Chung, F.-L. Search for Related Content PubMed PubMed Citation Articles by Yang, Y.-M. Articles by Chung, F.-L.

Inhibition of Benzo(a)pyrene-induced Lung Tumorigenesis in A/J Mice by Dietary N-Acetylcysteine Conjugates of Benzyl and Phenethyl Isothiocyanates during the Postinitiation Phase Is Associated with Activation of Mitogen-activated Protein Kinases and p53 Activity and Induction of Apoptosis¹

Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595 [Y-M. Y., C. C. C., W. D., S. A., F-L. C.], and Pathology and Toxicology [C-X. W., J. W.], Research Animal Facility [J. R.], Department of Medicine, New York Medical College, Valhalla, New York 10595 [J. W. C.]

Recent studies in cell culture have shown that isothiocyanates (ITCs) induce apoptosis via activation of mitogen-activated protein (MAP) kinases and p53 pathways, suggesting a potential for ITCs or their conjugates to inhibit tumorigenesis during the postinitiation phase. To evaluate whether ITC compounds administered after carcinogen treatment inhibit lung tumorigenesis, we investigated in A/J mice the effects of the N-acetylcysteine (NAC) conjugates of benzyl (BITC-NAC) and phenethyl ITC (PEITC-NAC) in the diet (15 µmol/g) administered after a single dose of 20 µmol benzo(a)pyrene [B(a)P]. The formation of lung adenomas was examined 140 days after B(a)P dosing. Both the BITC-NAC and PEITC-NAC-treated groups showed a significant reduction in lung tumor multiplicity from 6.1 ± 3.1 tumors/mouse in the B(a)P group fed the control diet to 3.7 ± 2.9 and 3.4 ± 2.7 tumors/mouse (P = 0.018 and 0.006, respectively). To investigate the mechanisms of tumor inhibition, lung tissues were obtained at 21, 84, and 140 days at interim sacrifices during the bioassay. These tissues showed a significant increase in apoptosis as determined by in situ end-labeling for both ITC-NAC-treated groups. The MAP kinase pathway was activated in the ITC-NAC-treated groups. The activation of c-Jun NH₂-terminal kinase was higher in the BITC-NAC and PEITC-NAC groups when compared with B(a)P-treated control. The phosphorylation of p38 and extracellular signal-regulated kinases (ErKs) 1 and 2 was also induced by these treatments. To determine the downstream target of MAP kinases, activator protein-1 (AP-1) and nuclear factor-B activities were evaluated by gel shift assay. The AP-1 binding activity was remarkably increased in lung tissue from both the BITC-NAC and PEITC-NAC groups. No change in nuclear factor-B binding activity was found, however. Phosphorylation of p53 was also higher than the constitutive levels in both ITC-NAC-treated groups, but no induction of p53 expression was detected. This study demonstrates the chemopreventive efficacy of the NAC conjugates of PEITC and BITC administered in the diet after a single dose of B(a)P for lung tumorigenesis and provides the first in vivo evidence that activation of MAP kinases, AP-1 transcription factors, p53 phosphorylation, and the induction of apoptosis may be involved in the chemopreventive activity of these compounds.

This article has been cited by other articles:

				A. Bommareddy, E.-R. Hahm, D. Xiao, A. A. Powolny, A. L. Fisher, Y. Jiang, and S. V. Singh Atg5 Regulates Phenethyl Isothiocyanate-Induced Autophagic and Apoptotic Cell Death in Human Prostate Cancer Cells Cancer Res., April 15, 2009; 69(8): 3704 - 3712. [Abstract] [Full Text] [PDF]

				T. E. Johnson, F. Kassie, M. G. O'Sullivan, M. Negia, T. E. Hanson, P. Upadhyaya, P. P. Ruvolo, S. S. Hecht, and C. Xing Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene-Induced Lung Tumorigenesis in A/J Mice Cancer Prevention Research, November 1, 2008; 1(6): 430 - 438. [Abstract] [Full Text] [PDF]

				D. Xiao, A. A. Powolny, and S. V. Singh Benzyl Isothiocyanate Targets Mitochondrial Respiratory Chain to Trigger Reactive Oxygen Species-dependent Apoptosis in Human Breast Cancer Cells J. Biol. Chem., October 31, 2008; 283(44): 30151 - 30163. [Abstract] [Full Text] [PDF]

				F. Kassie, I. Matise, M. Negia, D. Lahti, Y. Pan, R. Scherber, P. Upadhyaya, and S. S. Hecht Combinations of N-Acetyl-S-(N-2-Phenethylthiocarbamoyl)-L-Cysteine and myo-Inositol Inhibit Tobacco Carcinogen-Induced Lung Adenocarcinoma in Mice Cancer Prevention Research, September 1, 2008; 1(4): 285 - 297. [Abstract] [Full Text] [PDF]

				L. Mi, X. Wang, S. Govind, B. L. Hood, T. D. Veenstra, T. P. Conrads, D. T. Saha, R. Goldman, and F.-L. Chung The Role of Protein Binding in Induction of Apoptosis by Phenethyl Isothiocyanate and Sulforaphane in Human Non-Small Lung Cancer Cells Cancer Res., July 1, 2007; 67(13): 6409 - 6416. [Abstract] [Full Text] [PDF]

				N. Khan, F. Afaq, and H. Mukhtar Apoptosis by dietary factors: the suicide solution for delaying cancer growth Carcinogenesis, February 1, 2007; 28(2): 233 - 239. [Abstract] [Full Text] [PDF]

				D. Xiao, V. Vogel, and S. V. Singh Benzyl isothiocyanate-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species and regulated by Bax and Bak. Mol. Cancer Ther., November 1, 2006; 5(11): 2931 - 2945. [Abstract] [Full Text] [PDF]

				D. Xiao, K. L. Lew, Y. Zeng, H. Xiao, S. W. Marynowski, R. Dhir, and S. V. Singh Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential Carcinogenesis, November 1, 2006; 27(11): 2223 - 2234. [Abstract] [Full Text] [PDF]

				S. Sharma, P. Gao, and V. E. Steele The chemopreventive efficacy of inhaled oltipraz particulates in the B[a]P-induced A/J mouse lung adenoma model Carcinogenesis, August 1, 2006; 27(8): 1721 - 1727. [Abstract] [Full Text] [PDF]

				Y.-J. Surh, J. K. Kundu, H.-K. Na, and J.-S. Lee Redox-Sensitive Transcription Factors as Prime Targets for Chemoprevention with Anti-Inflammatory and Antioxidative Phytochemicals J. Nutr., December 1, 2005; 135(12): 2993S - 3001S. [Abstract] [Full Text] [PDF]

				Y.-M. Yang, M. Jhanwar-Uniyal, J. Schwartz, C. C. Conaway, H. D. Halicka, F. Traganos, and F.-L. Chung N-Acetylcysteine Conjugate of Phenethyl Isothiocyanate Enhances Apoptosis in Growth-Stimulated Human Lung Cells Cancer Res., September 15, 2005; 65(18): 8538 - 8547. [Abstract] [Full Text] [PDF]

				C. C. Conaway, C.-X. Wang, B. Pittman, Y.-M. Yang, J. E. Schwartz, D. Tian, E. J. McIntee, S. S. Hecht, and F.-L. Chung Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice Cancer Res., September 15, 2005; 65(18): 8548 - 8557. [Abstract] [Full Text] [PDF]

				J. W. FINLEY Proposed Criteria for Assessing the Efficacy of Cancer Reduction by Plant Foods Enriched in Carotenoids, Glucosinolates, Polyphenols and Selenocompounds Ann. Bot., June 1, 2005; 95(7): 1075 - 1096. [Abstract] [Full Text] [PDF]

				D. Xiao, Y. Zeng, S. Choi, K. L. Lew, J. B. Nelson, and S. V. Singh Caspase-Dependent Apoptosis Induction by Phenethyl Isothiocyanate, a Cruciferous Vegetable-Derived Cancer Chemopreventive Agent, Is Mediated by Bak and Bax Clin. Cancer Res., April 1, 2005; 11(7): 2670 - 2679. [Abstract] [Full Text] [PDF]

				S. Choi and S. V. Singh Bax and Bak Are Required for Apoptosis Induction by Sulforaphane, a Cruciferous Vegetable-Derived Cancer Chemopreventive Agent Cancer Res., March 1, 2005; 65(5): 2035 - 2043. [Abstract] [Full Text] [PDF]

				J. W. Chiao, H. Wu, G. Ramaswamy, C. C. Conaway, F.-L. Chung, L. Wang, and D. Liu Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest Carcinogenesis, August 1, 2004; 25(8): 1403 - 1408. [Abstract] [Full Text] [PDF]

				L. Tang and Y. Zhang Dietary Isothiocyanates Inhibit the Growth of Human Bladder Carcinoma Cells J. Nutr., August 1, 2004; 134(8): 2004 - 2010. [Abstract] [Full Text] [PDF]

				R. Hu, V. Hebbar, B.-R. Kim, C. Chen, B. Winnik, B. Buckley, P. Soteropoulos, P. Tolias, R. P. Hart, and A.-N. T. Kong In Vivo Pharmacokinetics and Regulation of Gene Expression Profiles by Isothiocyanate Sulforaphane in the Rat J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 263 - 271. [Abstract] [Full Text] [PDF]

				D. Xiao, C. S. Johnson, D. L. Trump, and S. V. Singh Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells Mol. Cancer Ther., May 1, 2004; 3(5): 567 - 576. [Abstract] [Full Text] [PDF]

				J. M. Pullar, S. J. Thomson, M. J. King, C. I. Turnbull, R. G. Midwinter, and M. B. Hampton The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis Carcinogenesis, May 1, 2004; 25(5): 765 - 772. [Abstract] [Full Text] [PDF]

				A. V. Singh, D. Xiao, K. L. Lew, R. Dhir, and S. V. Singh Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo Carcinogenesis, January 1, 2004; 25(1): 83 - 90. [Abstract] [Full Text] [PDF]

				Y. Zhang, L. Tang, and V. Gonzalez Selected isothiocyanates rapidly induce growth inhibition of cancer cells Mol. Cancer Ther., October 1, 2003; 2(10): 1045 - 1052. [Abstract] [Full Text]

				S. K. Srivastava, D. Xiao, K. L. Lew, P. Hershberger, D. M. Kokkinakis, C. S. Johnson, D. L. Trump, and S. V. Singh Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits growth of PC-3 human prostate cancer xenografts in vivo Carcinogenesis, October 1, 2003; 24(10): 1665 - 1670. [Abstract] [Full Text] [PDF]

				R. Hu, B. R. Kim, C. Chen, V. Hebbar, and A.-N.T. Kong The roles of JNK and apoptotic signaling pathways in PEITC-mediated responses in human HT-29 colon adenocarcinoma cells Carcinogenesis, August 1, 2003; 24(8): 1361 - 1367. [Abstract] [Full Text] [PDF]

				K. Akagi, M. Sano, K. Ogawa, M. Hirose, H. Goshima, and T. Shirai Involvement of Toxicity as an Early Event in Urinary Bladder Carcinogenesis Induced by Phenethyl Isothiocyanate, Benzyl Isothiocyanate, and Analogues in F344 Rats Toxicol Pathol, June 1, 2003; 31(4): 388 - 396. [Abstract] [PDF]

				D. Xiao, S. K. Srivastava, K. L. Lew, Y. Zeng, P. Hershberger, C. S. Johnson, D. L. Trump, and S. V. Singh Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits proliferation of human prostate cancer cells by causing G2/M arrest and inducing apoptosis Carcinogenesis, May 1, 2003; 24(5): 891 - 897. [Abstract] [Full Text] [PDF]

				S. Sugiura, K. Ogawa, M. Hirose, F. Takeshita, M. Asamoto, and T. Shirai Reversibility of proliferative lesions and induction of non-papillary tumors in rat urinary bladder treated with phenylethyl isothiocyanate Carcinogenesis, March 1, 2003; 24(3): 547 - 553. [Abstract] [Full Text] [PDF]

				F. Kassie, M. Uhl, S. Rabot, B. Grasl-Kraupp, R. Verkerk, M. Kundi, M. Chabicovsky, R. Schulte-Hermann, and S. Knasmuller Chemoprevention of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced colonic and hepatic preneoplastic lesions in the F344 rat by cruciferous vegetables administered simultaneously with the carcinogen Carcinogenesis, February 1, 2003; 24(2): 255 - 261. [Abstract] [Full Text] [PDF]

				S. S. Hecht, P. Upadhyaya, M. Wang, R. L. Bliss, E. J. McIntee, and P. M.J. Kenney Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination Carcinogenesis, September 1, 2002; 23(9): 1455 - 1461. [Abstract] [Full Text] [PDF]

				D. Xiao and S. V. Singh Phenethyl Isothiocyanate-induced Apoptosis in p53-deficient PC-3 Human Prostate Cancer Cell Line Is Mediated by Extracellular Signal-regulated Kinases Cancer Res., July 1, 2002; 62(13): 3615 - 3619. [Abstract] [Full Text] [PDF]

				C. Krul, C. Humblot, C. Philippe, M. Vermeulen, M. van Nuenen, R. Havenaar, and S. Rabot Metabolism of sinigrin (2-propenyl glucosinolate) by the human colonic microflora in a dynamic in vitro large-intestinal model Carcinogenesis, June 1, 2002; 23(6): 1009 - 1016. [Abstract] [Full Text] [PDF]