Carcinogenesis

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Carcinogenesis, Vol. 21, No. 12, 2287-2291, December 2000
© 2000 Oxford University Press

SHORT COMMUNICATION

Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate

Fung-Lung Chung^1,3, C.Clifford Conaway¹, C.V. Rao² and Bandaru S. Reddy²

¹ Division of Carcinogenesis and Molecular Epidemiology and
² Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, NY 10595, USA

	Abstract

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Epidemiological studies have linked consumption of broccoli to a reduced risk of colon cancer in individuals with the glutathione S-transferase M1 (GSTM1) null genotype. GSTs are involved in excretion and elimination of isothiocyanates (ITCs), which are major constituents of broccoli and other cruciferous vegetables and have cancer chemopreventive potential, so it is speculated that ITCs may play a role in protection against human colon cancer. However, there is a lack of data from animal studies to support this. We carried out a bioassay to examine whether sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), major ITCs in broccoli and watercress, respectively, and their corresponding N-acetylcysteine (NAC) conjugates, show any chemopreventive activity towards azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in F344 rats. Groups of six male F344 rats were treated with AOM subcutaneously (15 mg/kg body wt) once weekly for 2 weeks. SFN and PEITC and their NAC conjugates were administered by gavage either three times weekly for 8 weeks (5 and 20 µmol, respectively) after AOM dosing (post-initiation stage) or once daily for 3 days (20 and 50 µmol, respectively) before AOM treatment (initiation stage). The bioassay was terminated on week 10 after the second AOM dosing and ACF were quantified. SFN, SFN-NAC, PEITC and PEITC-NAC all significantly reduced the formation of total ACF from 153 to 100–116 (P < 0.01) and multicrypt foci from 52 to 27–38 (more than four crypts/focus; P < 0.05) during the post-initiation treatment. However, only SFN and PEITC were effective during the initiation phase, reducing the total ACF from 153 to 109–115 (P < 0.01) and multicrypt foci from 52 to 35 (more than four crypts/focus; P < 0.05). The NAC conjugates were inactive as anti-initiators against AOM-induced ACF. These findings provide important laboratory evidence for a potential role of SFN and PEITC in the protection against colon cancer.

Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; BITC, benzyl isothiocyanate; CYP, cytochrome P450; GST, glutathione S-transferase; ITCs, isothiocyanates; NAC, N-acetylcysteine; PEITC, phenethyl isothiocyanate; SFN, sulforaphane.

	Introduction

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A recent case–control study reported that broccoli consumption is linked to a lowered risk of colon cancer and that the protective effect is especially evident in individuals with a glutathione S-transferase (GST) M1 null genotype (1). Because GSTs facilitate the conjugation of isothiocyanates (ITCs), resulting in their excretion as N-acetylcysteine (NAC) conjugates via the mercapturic acid pathway, it has been suggested that the ITC compounds in broccoli may play a role in protection against human colon cancer (1,2). Sulforaphane (SFN) is the predominant ITC found in broccoli. It has been studied for its chemopreventive potential primarily due to its activity as an inducer of phase II enzymes involved in carcinogen detoxification and elimination (3). Although it has been reported that SFN inhibits carcinogen-induced mammary gland tumorigenesis (4,5), no animal data are yet available regarding the effects of SFN on colon tumorigenesis. Several laboratory animal studies have shown that phenethyl ITC (PEITC), a principal constituent of watercress, is a potent chemopreventive agent for cancers of the breast, lung, and esophagus (6–8). However, there is only limited information about its protective effect against colon cancer. Given current data supporting ITCs as chemopreventive agents in a variety of tumor models, it is possible that SFN and PEITC would protect against colon tumor development. The present bioassay was designed to determine whether SFN and PEITC can inhibit the formation of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in Fischer 344 rats. ACF have been recognized as an early preneoplastic lesion of colon cancer (9–11) and agents that inhibit colonic ACF formation generally show chemopreventive activity against colon cancer (12). We also included in this study the NAC conjugates of SFN and PEITC since our previous studies showed that certain ITC–NAC conjugates are promising chemopreventive agents for lung tumorigenesis, probably by a gradual release of the parent ITCs via a dissociation reaction (13,14). The structures of SFN and PEITC and their NAC conjugates are shown in Figure 1. SFN and PEITC or their NAC conjugates were administered in two treatment regimens, either after AOM treatment (post-initiation) or before AOM treatment (initiation) in order to define better the possible mechanism of action.

View larger version (13K): [in this window] [in a new window]   Fig. 1. Structures of SFN and PEITC and their NAC conjugates.

 
Male F344 rats were obtained from Charles River (Kingston, NY). They were fed AIN-76A diet (5% corn oil) and tap water ad libitum. Animals were maintained under standard conditions (12 h light/12 h dark cycle, 50% relative humidity at 21°C). At 6 weeks of age, they were randomly divided into groups of six rats as shown in Table I, except for the control groups (groups 10–14), which included three animals each. PEITC and D,L-SFN (purity >99% and >97%, respectively) were purchased from Aldrich Chemical Co. (Milwaukee, WI) and LTK Labs, Inc. (St Paul, MN). The corresponding NAC conjugates were prepared by a published method (15). The structures were verified by their proton NMR spectra. The purity of the conjugates was >97% as determined by high-performance liquid chromatography. AOM obtained from Ash-Stevens (Detroit, MI) was dissolved in saline and administered at 15 mg/kg body wt subcutaneously twice (7 days between the two injections), a previously established treatment regimen for the induction of colon tumor (16). SFN and PEITC in corn oil and NAC conjugates in saline (10% dimethylsulfoxide) were given by gavage. The high cost of SFN prohibited administration of the compound in the diet. For the post-initiation treatment, groups 2–5 were given 5 µmol SFN or PEITC or 20 mmol of the NAC conjugates, three doses each week for 8 weeks, beginning two days after the last dose of AOM. The higher doses of the NAC conjugates were given because of their gradual release of parent compounds and lower toxicity. For the assay of anti-initiation activity, groups 6–9 were treated with three doses of ITC compounds (20 µmol ITC or 50 µmol ITC–NAC) once daily; the last dose was given 2 h before AOM dosing. This dosing regimen was repeated during the second week of AOM dosing. This pre-treatment protocol was adapted based on earlier studies on mammary tumor and lung tumor models (17,18). Groups 10–13 were treated with ITCs (5 µmol/dose) or the conjugates (20 µmol/dose) only, three times weekly for 8 weeks. The bioassay was terminated at week 10 after the second AOM treatment. All animals were killed by CO₂ asphyxiation. The colons were excised, fixed in buffered formalin and processed for microscopic examination; ACF were recorded using a standard procedure described previously (19). ACF were distinguished from the surrounding normal crypts by their increased size, significantly increased distance from lamina to basal surface of cells and the easily discernible pericryptal zone. For statistical analysis, means were compared among the groups using one-way analysis of variance (ANOVA) followed by Fisher's protected t-test.

View this table: [in this window] [in a new window]   Table I. Effects of SFN and PEITC on the formation of aberrant crypt foci induced by AOM

 
No significant differences in body weights were seen in any of the treated groups compared with the control group, indicating that doses of ITCs and the conjugates used did not cause overt toxicity (Figure 2). This bioassay showed that post-treatment with SFN and PEITC by oral administration at 5 µmol three times weekly for 8 weeks and their NAC conjugates at 20 µmol by the same regimen inhibited formation of ACF. These treatments reduced the total number of ACF from 153 to 100–116 (P < 0.01) and reduced the number of multicrypt foci (more than four crypts/focus) from 52 to 27–37 (P < 0.05) as shown in Table I (groups 1–5). Because the ITC conjugates are presumably less toxic than the parent ITCs, the doses of the conjugates were four times that of SFN and PEITC (5,20). However, we did not find significant differences in the inhibition of ACF between the ITCs and their NAC conjugates, suggesting that the conjugates themselves are not as active. Similar dose–effect relationships were observed previously between parent ITCs and their conjugates towards the inhibition of lung tumorigenesis (13). These results, together with those from our earlier studies (21,22), suggest that ITC conjugates render their inhibitory activity in part by deconjugation to the parent ITCs. Although the mechanism of inhibition of ACF at the post-initiation phase is not currently clear, studies have shown that PEITC and related ITCs induce p53-dependent or c-Jun kinase-mediated apoptosis in cultured tumor cells (23–25). More recently it has been reported that SFN induces cell cycle arrest in HT29 human colon cancer cells (26). The growth arrest, followed by cell death via apoptosis, appeared to be associated with expression of cyclins A and B1. In addition, NAC produced by deconjugation is a known antioxidant and has been recently shown to inhibit mouse fibroblast cell proliferation by blocking cell in G₁ phase (27). All these activities could have contributed to the inhibition of ACF formation during post-initiation.

View larger version (21K): [in this window] [in a new window]   Fig. 2. Growth curves of the treated and the control groups during the bioassay.

 
As shown previously by us and others, pretreatment of animals with PEITC and other related ITCs blocked chemical-induced tumorigenicity by inhibiting cytochrome P450 (CYP) enzymes responsible for the activation of carcinogens, and consequently reducing DNA damage (28–30). Using the pretreatment regimen, we investigated the effects of SFN and PEITC on AOM-induced colonic ACF formation in Fischer rats. Pretreatment with SFN or PEITC significantly decreased the total number of ACF from 153 to 109 (P < 0.001) or 115 (P < 0.01), respectively, and multicrypt foci (more than four crypts) from 52 to 35 (P < 0.05) for both compounds (Table I). We have previously shown that PEITC and PEITC–NAC inhibit N,N-dimethylnitrosamine (NDMA) demethylase (CYP2E1) in rat liver microsomes (21). Like NDMA, AOM is metabolically activated by CYP2E1 to methyazoxymethanol, which can yield a DNA methylating species (31). Thus, inhibition of CYP2E1 by these agents in the rat liver may constitute an important mechanism of inhibition, because CYP enzyme activity in colonic tissue is low compared with that in liver (32). SFN–NAC also reduced total ACF to 120 (P < 0.01); however, it had no significant effect on multicrypt foci (those with more than four crypts/focus; 15% inhibition). PEITC–NAC, on the other hand, appeared to enhance ACF formation [total number of ACF was 198 (P < 0.001); number of multicrypt foci was 74 (P < 0.05)] (Table I). The adverse effect caused by PEITC–NAC is somewhat unexpected in view of the inhibition by its parent ITC. At present, it is not clear why there is such a sharp contrast in ACF formation between PEITC–NAC and the other ITC compounds studied here. Previously, it has been reported that PEITC given in the diet at 0.1% for 32 weeks appeared to promote bladder cancer development in rats pretreated with carcinogens (33). This dose is considerably higher than the doses used in the present study. Phenylhexyl ITC, a synthetic homolog of PEITC, is a potent inhibitor of lung tumorigenesis in rats and mice, whereas it enhanced colon and esophagus tumorigenesis in rats, possibly due to its tissue cytotoxicity at the dose level studied (34–37). These results illustrate the importance of choosing the appropriate dose range for specific tissues in chemoprevention studies.

Evidence from epidemiological studies suggests an association between consumption of cruciferous vegetables and a reduced risk of colon cancer (38). Although the beneficial effects may result from the combined effects of a number of compounds in these vegetables, the exact role of each compound that contributes to the protective effects needs to be identified more clearly. Ample data from laboratory animal studies have shown that ITCs, major constituents of cruciferous vegetables, are promising chemopreventive agents against cancers at various sites, including lung, esophagus, liver, mammary, pancreas and bladder (3,28,39). These laboratory results support a potential role of dietary ITCs in reducing the risk of certain human cancers. Considering the natural abundance of SFN and PEITC in broccoli and watercress [it is estimated that an individual's intake of SFN or PEITC after ingesting 100 g (wet weight) of broccoli or watercress can range from 50 to 200 µmol (40–43)], and their potential as chemopreventive agents, it is surprising that little is known about the effects of these agents on colon tumorigenesis. A lower homolog of PEITC, benzyl ITC (BITC) has been shown to reduce colon tumor incidence in AOM treated rats during the initiation phase, but not during the post-initiation phase (44). Another short-term study, however, has reported that both PEITC and BITC given in the diet at similar doses throughout the bioassay did not affect ACF formation (12). By contrast, the present study has demonstrated that both PEITC and SFN inhibit colonic ACF, independent of whether they are administered before or after exposure to carcinogen. These data, thus, support a potential protective role of SFN and PEITC in colon cancer and are consistent with the epidemiological observation that consumption of certain cruciferous vegetables reduces the risk of colon cancer in individuals with GSTM1 null genotype. These findings warrant further investigations of the mechanisms of action and preclinical efficacy of these agents.

	Notes

 
³ To whom correspondence should be addressed Email: chungahf{at}aol.com

	Acknowledgments

 
We would like to thank Joanne Braley and Joel Reinhardt of the Research Animal Facility at the American Health Foundation for their expert work in animal handling and care. We also thank Barbara Simi for her excellent technical assistance on quantifying aberrant crypt foci and Brian Pittman for statistical analysis. This work was supported by NCI grant CA46535. This is paper number 31 in the series `Dietary Inhibitors of Chemical Carcinogenesis'.

	References

Top Abstract Introduction References

 

1. Lin,H.J., Probst-Hensch,N.M., Louie,A.D., Kau,I.H., Witte,J.S., Ingles,S.A., Frankl,H.D., Lee,E.R. and Haile,R.W. (1998) Glutathione transferase null genotype, broccoli and lower prevalence of colorectal adenomas. Cancer Epidemiol. Biomark. Prev., 7, 647–652.[Abstract]
2. Ketterer,B. (1998): Dietary isothiocyanates as confounding factors in the molecular epidemiology of colon cancer. Commentary re: H.J. Lin et al., Glutathione transferase null genotype, broccoli and lower prevalence of colorectal adenomas. Cancer Epidemiol. Biomark. Prev., 7, 647–652.[Abstract]
3. Zhang,Y. and Talalay,P. (1994) Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res., 54 (suppl.), 1976s–1986s.[Abstract]
4. Zhang,Y., Kensler,T.W., Cho,C.-G., Posner,G.H. and Talalay,P. (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc. Natl Acad. Sci. USA, 91, 3147–3150.[Abstract]
5. Gerhauser,C., You,M., Liu,J., Moriarty,R.M., Hawthorne,M., Mehta,R.G., Moon,R.C. and Pezzuto,J.M. (1997) Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes. Cancer Res, 57, 272–278.[Abstract]
6. Wattenberg,L.W. (1977) Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J. Natl Cancer Inst., 58, 396–398.
7. Chung,F.-L., Morse,M.A. and Eklind,K.I. (1992) New potential chemopreventive agents for lung carcinogenesis of tobacco-specific nitrosamine. Cancer Res., 52, 2719s–2722s.[Abstract]
8. Stoner,G.D., Morrissey,D.T., Heur,Y.-H., Daniel,E.M., Galati,A.J. and Wagner,S.A. (1991) Inhibitory effects of phenethyl isothiocyanate on N-nitrosobenzylmethylamine carcinogenesis in the rat esophagus. Cancer Res., 51, 2063–2068.[Abstract]
9. Mclellan,E.A. and Bird,R.P. (1988) Aberrant crypts: potential preneoplastic lesions in the murine colon. Cancer Res., 48, 6187–6192.[Abstract]
10. Mclellan,E., Medline,A. and Bird,R.P. (1991) Sequential analyses of the growth and morphological characteristics of aberrant crypt foci-putative preneoplastic lesions. Cancer Res., 51, 5270–5274.[Abstract]
11. Pretlow,T.P., O'Riordan,M.A., Pretlow,T.G. and Stellato,T.A. (1992) Aberrant crypts in human colonic mucosa: putative preneoplastic lesions. J. Cell Biochem., 16G (suppl.), 55–62.
12. Wargovich,M.J., Chen,C.-D., Jimenez,A., Steele,V.E., Velasco,M., Stephens,L.C., Price,R., Gray,K. and Kelloff,G.J. (1996) Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat. Cancer Epidemiol. Biomark. Prev., 5, 355–360.[Abstract]
13. Jiao,D., Smith,T.J., Yang,C.S., Pittman,B., Desai,D., Amin,S. and Chung,F.-L. (1997) Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis. Carcinogenesis, 18, 2143–2147.[Abstract]
14. Chung,F.-L., Jiao,D., Conaway,C.C., Smith,T.J., Yang,C.S. and Yu,M.C. (1997) Chemopreventive potential of thiol conjugates of isothiocyanates for lung cancer and a urinary biomarker of dietary isothiocyanates. J. Cell. Biochem. (suppl.), 27, 76–85.
15. Kassahun,K., Davis,M., Hu,P., Martin,B. and Baillie,T. (1997) Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase 1 metabolites and glutathione conjugates. Chem. Res. Toxicol., 10, 1228–1233.[Medline]
16. Reddy,B.S. and Maruyama,H. (1986) Effect of different levels of dietary corn oil and lard during the initiation phase of colon carcinogenesis in F344 rats. J. Natl Cancer Inst., 77, 815–822.[Medline]
17. Wattenberg,L.W. (1977) Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J. Natl Cancer Inst., 58, 396–398.
18. Morse,M.A., Amin,S.G., Hecht,S.S. and Chung,F.-L. (1989) Effects of aromatic isothiocyanates on tumorigenicity, O⁶-methylguanine formation and metabolism of the tobacco-specific nitrosamine 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung. Cancer Res., 49, 2894–2897.[Abstract]
19. Reddy,B.S., Rao,C.V. and Seibert,K. (1996) Evaluation of cycloxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. Cancer Res., 56, 4566–4569.[Abstract]
20. Zheng,G.-Q., Kenney,P.M. and Lam,L.K.T. (1992) Phenylalkyl isothiocyanate-cysteine conjugates as glutathione S-transferase stimulating agents. J. Med. Chem., 35, 185–188.[Medline]
21. Jiao,D., Conaway,C.C., Wang,M.-H., Yang,C.S., Koehl,W. and Chung,F.-L. (1996) Inhibition of N-nitrosodimethylamine demethylase in rat and human liver microsomes by isothiocyanates and their glutathione, L-cysteine and N-acetyl-L-cysteine conjugates. Chem. Res. Toxicol., 9, 932–938.[Medline]
22. Conaway,C.C., Jiao,D. and Chung,F.-L. (1996) Inhibition of rat liver cytochrome P450 isozymes by isothiocyanates and their conjugates: A structure–activity relationship study. Carcinogenesis, 16, 2423–2427.[Abstract]
23. Chen,Y.-R., Wang,W., Kong,A.-N.T. and Tan,T.-H. (1998) Molecular mechanisms of c-jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates. J. Biol. Chem., 273, 1769–1775.[Abstract/Full Text]
24. Huang,C., Ma,W.-Y., Li,J., Hecht,S.S. and Dong,Z. (1998) Essential role of p53 in phenethyl isothiocyanate-induced apoptosis. Cancer Res., 58, 4102–4106.[Abstract]
25. Yu,R., Mandlekar,S., Harvey,K.J., Ucker,D.S. and Kong,A.-N.T. (1998) Chemopreventive isothiocyanates induce apoptosis and Caspase-3-like protease activity. Cancer Res., 58, 402–408.[Abstract]
26. Gamet-Payrastre,L., Li,P., Lumeau,S., Cassar,G., Dupont,M.-A., Chevolleau,S., Gasc,N., Tulliez,J. and Terce,F. (2000) Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res., 60, 1426–1433.[Abstract/Full Text]
27. Sekharam,M., Trotti,A., Cunnick,J.M. and Wu,J. (1998) Suppression of fibroblast cell cycle progression in G1 phase by N-acetylcysteine. Toxicol. Appl. Pharm., 149, 210–216.
28. Chung,F.-L. (1992) Chemoprevention of lung carcinogenesis by aromatic isothiocyanates. In Wattenberg,L., Lipkin,M., Boone,C.W. and Kelloff,G.J. (eds), Cancer Chemoprevention, CRC Press Inc., Boca Raton, FL. 227–245.
29. Guo,Z., Smith,T.J., Wang,E., Eklind,K.I., Chung,F.-L. and Yang,C.S. (1993) Structure–activity relationships of arylalkyl isothiocyanates for the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and the modulation of xenobiotic-metabolizing enzymes in rats and mice. Carcinogenesis, 14, 1167–1173.[Abstract]
30. Wilkinson,J.T., Morse,M.A., Kresty,L.A. and Stoner,G.D. (1995) Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates. Carcinogenesis, 16, 1011–1015.[Abstract]
31. Sohn,O.S., Fiala,E.S., Puz,C., Hamilton,S.R. and Williams,G.M. (1987) Enhancement of rat liver microsomal metabolism of azoxymethane to methylazoxymethanol by chronic ethanol administration: Similarity to the microsomal metabolism on N-nitrosodimethylamine. Cancer Res., 47, 3123–3129.[Abstract]
32. Strobel,H.W., Fang,W.-F. and Oshinsky,R.J. (1980) Role of colonic cytochrome P-450 in large bowel carcinogenesis. Cancer, 45, 1060–1065.[Medline]
33. Hirose,M., Yamaguchi,T., Kimoto,N., Ogawa,K., Futakuchi,M., Sano,M. and Shirai,T. (1998) Strong promoting activity of phenylethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesis in F344 male rats. Int. J. Cancer, 77, 773–777.[Medline]
34. Jiao,D., Eklind,K.I., Choi,C.-I., Desai,D.H., Amin,S.G. and Chung,F.-L. (1994) Structure–activity relationships of isothiocyanates as mechanism-based inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice. Cancer Res., 54, 4327–4333.[Abstract]
35. Chung,F.L., Kelloff,G., Steele,V., Pittman,B., Zang,E., Jiao,D., Rigotty,J., Choi,C.-I. and Rivenson,A. (1996) Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetylcysteine for lung tumorigenesis in Fischer rats. Cancer Res., 56, 772–778.[Abstract]
36. Rao,C.V., Rivenson,A., Simi,B., Zang,E., Hamid,R., Kelloff,G.J., Steele,V. and Reddy,B.S. (1995) Enhancement of experimental colon carcinogenesis by dietary 6-phenylhexyl isothiocyanate. Cancer Res., 55, 4311–4318.[Abstract]
37. Stoner,G.D., Siglin,J.C., Morse,M.A., Desai,D.H., Amin,S.G., Kresty,L.A., Toburen,A.L., Heffner,E.M. and Francis,D.J. (1995) Enhancement of esophageal carcinogenesis in male F344 rats by dietary phenylhexyl isothiocyanate. Carcinogenesis, 16, 2473–2476.[Abstract]
38. Steinmetz,K.A. and Potter,J.D. (1991) Vegetables, fruits and cancer, I. Epidemiology. Cancer Causes Control, 2, 325–357.[Medline]
39. Hecht,S.S. Chemoprevention by isothiocyanates. (1995) J. Cell. Biochem. (Suppl.), 22, 195–209.
40. Chung,F.-L., Morse,M.A., Eklind,K.I. and Lewis,J. (1992) Quantitation of human uptake of the anticarcinogen phenethyl isothiocyanate after a watercress meal. Cancer Epidemiol. Biomarkers Prev., 1, 383–388.[Abstract]
41. Howard,L.A., Jeffery,E.H., Wallig,M.A. and Klein,B.P. (1997) Retention of phytochemicals in fresh and processed broccoli. J. Food Sci., 62, 1098–1104.
42. Shapiro,T.A., Fahey,J.W., Wade,K.L., Stephenson,K.K. and Talalay,P. (1998) Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol. Biomarkers Prev., 7, 1091–1100.[Abstract]
43. Conaway,C.C., Getahun,S.M., Liebes,L.L., Pusateri,D.J., Topham,D.K.W., Botero-Omary,M. and Chung,F.-L. Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli. Nutr. Cancer, in press.
44. Sugie,S., Okamoto,K., Okumura,A., Tanaka,T. and Mori,H. (1994) Inhibitory effects of benzyl thiocyanate and benzyl isothiocyanate on methylazoxymethanol acetate-induced intestinal carcinogenesis in rats. Carcinogenesis, 15, 1555–1560.[Abstract]

Received March 8, 2000; revised August 18, 2000; accepted August 29, 2000.

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				C. Zhou, E.-J. Poulton, F. Grun, T. K. Bammler, B. Blumberg, K. E. Thummel, and D. L. Eaton The Dietary Isothiocyanate Sulforaphane Is an Antagonist of the Human Steroid and Xenobiotic Nuclear Receptor Mol. Pharmacol., January 1, 2007; 71(1): 220 - 229. [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]

				R. Zhang, S. Loganathan, I. Humphreys, and S. K. Srivastava Benzyl Isothiocyanate-Induced DNA Damage Causes G2/M Cell Cycle Arrest and Apoptosis in Human Pancreatic Cancer Cells J. Nutr., November 1, 2006; 136(11): 2728 - 2734. [Abstract] [Full Text] [PDF]

				R. Hu, T. O. Khor, G. Shen, W.-S. Jeong, V. Hebbar, C. Chen, C. Xu, B. Reddy, K. Chada, and A.-N. T. Kong Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane, a natural product derived from cruciferous vegetable Carcinogenesis, October 1, 2006; 27(10): 2038 - 2046. [Abstract] [Full Text] [PDF]

				T.-a. Matsui, Y. Sowa, T. Yoshida, H. Murata, M. Horinaka, M. Wakada, R. Nakanishi, T. Sakabe, T. Kubo, and T. Sakai Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells Carcinogenesis, September 1, 2006; 27(9): 1768 - 1777. [Abstract] [Full Text] [PDF]

				C. Xu, M.-T. Huang, G. Shen, X. Yuan, W. Lin, T. O. Khor, A. H. Conney, and A.-N. T. Kong Inhibition of 7,12-Dimethylbenz(a)anthracene-Induced Skin Tumorigenesis in C57BL/6 Mice by Sulforaphane Is Mediated by Nuclear Factor E2-Related Factor 2 Cancer Res., August 15, 2006; 66(16): 8293 - 8296. [Abstract] [Full Text] [PDF]

				C. Xu, X. Yuan, Z. Pan, G. Shen, J.-H. Kim, S. Yu, T. O. Khor, W. Li, J. Ma, and A.-N. T. Kong Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Mol. Cancer Ther., August 1, 2006; 5(8): 1918 - 1926. [Abstract] [Full Text] [PDF]

				A. Herman-Antosiewicz, D. E. Johnson, and S. V. Singh Sulforaphane Causes Autophagy to Inhibit Release of Cytochrome c and Apoptosis in Human Prostate Cancer Cells Cancer Res., June 1, 2006; 66(11): 5828 - 5835. [Abstract] [Full Text] [PDF]

				M. C. Myzak, K. Hardin, R. Wang, R. H. Dashwood, and E. Ho Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells Carcinogenesis, April 1, 2006; 27(4): 811 - 819. [Abstract] [Full Text] [PDF]

				E. Bertl, H. Bartsch, and C. Gerhauser Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol. Cancer Ther., March 1, 2006; 5(3): 575 - 585. [Abstract] [Full Text] [PDF]

				C. Xu, G. Shen, X. Yuan, J.-h. Kim, A. Gopalkrishnan, Y.-S. Keum, S. Nair, and A.-N. T. Kong ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells Carcinogenesis, March 1, 2006; 27(3): 437 - 445. [Abstract] [Full Text] [PDF]

				A. Y.A. Plate and D. D. Gallaher Effects of Indole-3-Carbinol and phenethyl isothiocyanate on colon carcinogenesis induced by azoxymethane in rats Carcinogenesis, February 1, 2006; 27(2): 287 - 292. [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]

				S. V. Singh, S. K. Srivastava, S. Choi, K. L. Lew, J. Antosiewicz, D. Xiao, Y. Zeng, S. C. Watkins, C. S. Johnson, D. L. Trump, et al. Sulforaphane-induced Cell Death in Human Prostate Cancer Cells Is Initiated by Reactive Oxygen Species J. Biol. Chem., May 20, 2005; 280(20): 19911 - 19924. [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]

				N.-A. Pham, J. W. Jacobberger, A. D. Schimmer, P. Cao, M. Gronda, and D. W. Hedley The dietary isothiocyanate sulforaphane targets pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells and inhibits tumor growth in severe combined immunodeficient mice Mol. Cancer Ther., October 1, 2004; 3(10): 1239 - 1248. [Abstract] [Full Text] [PDF]

				S. K. Srivastava and S. V. Singh Cell cycle arrest, apoptosis induction and inhibition of nuclear factor kappa B activation in anti-proliferative activity of benzyl isothiocyanate against human pancreatic cancer cells Carcinogenesis, September 1, 2004; 25(9): 1701 - 1709. [Abstract] [Full Text] [PDF]

				M. C. Myzak, P. A. Karplus, F.-L. Chung, and R. H. Dashwood A Novel Mechanism of Chemoprotection by Sulforaphane: Inhibition of Histone Deacetylase Cancer Res., August 15, 2004; 64(16): 5767 - 5774. [Abstract] [Full Text] [PDF]

				T. K. Smith, E. K. Lund, M. L. Parker, R. G. Clarke, and I. T. Johnson Allyl-isothiocyanate causes mitotic block, loss of cell adhesion and disrupted cytoskeletal structure in HT29 cells Carcinogenesis, August 1, 2004; 25(8): 1409 - 1415. [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]

				Y. Zhang and G. B. Gordon A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway Mol. Cancer Ther., July 1, 2004; 3(7): 885 - 893. [Abstract] [Full Text] [PDF]

				S. V. Singh, A. Herman-Antosiewicz, A. V. Singh, K. L. Lew, S. K. Srivastava, R. Kamath, K. D. Brown, L. Zhang, and R. Baskaran Sulforaphane-induced G2/M Phase Cell Cycle Arrest Involves Checkpoint Kinase 2-mediated Phosphorylation of Cell Division Cycle 25C J. Biol. Chem., June 11, 2004; 279(24): 25813 - 25822. [Abstract] [Full Text] [PDF]

				A.-S. Keck and J. W. Finley Cruciferous Vegetables: Cancer Protective Mechanisms of Glucosinolate Hydrolysis Products and Selenium Integr Cancer Ther, March 1, 2004; 3(1): 5 - 12. [Abstract] [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]

				B.-R. Kim, R. Hu, Y.-S. Keum, V. Hebbar, G. Shen, S. S. Nair, and A-N. T. Kong Effects of Glutathione on Antioxidant Response Element-Mediated Gene Expression and Apoptosis Elicited by Sulforaphane Cancer Res., November 1, 2003; 63(21): 7520 - 7525. [Abstract] [Full Text] [PDF]

				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]

				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]

				A. Seow, J.-M. Yuan, C.-L. Sun, D. Van Den Berg, H.-P. Lee, and M. C. Yu Dietary isothiocyanates, glutathione S-transferase polymorphisms and colorectal cancer risk in the Singapore Chinese Health Study Carcinogenesis, December 1, 2002; 23(12): 2055 - 2061. [Abstract] [Full Text] [PDF]

				R. K. Thimmulappa, K. H. Mai, S. Srisuma, T. W. Kensler, M. Yamamoto, and S. Biswal Identification of Nrf2-regulated Genes Induced by the Chemopreventive Agent Sulforaphane by Oligonucleotide Microarray Cancer Res., September 15, 2002; 62(18): 5196 - 5203. [Abstract] [Full Text] [PDF]

				F. Kassie, S. Rabot, M. Uhl, W. Huber, H. M. Qin, C. Helma, R. Schulte-Hermann, and S. Knasmuller Chemoprotective effects of garden cress (Lepidium sativum) and its constituents towards 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ)-induced genotoxic effects and colonic preneoplastic lesions Carcinogenesis, July 1, 2002; 23(7): 1155 - 1161. [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]

				J. W. Fahey, X. Haristoy, P. M. Dolan, T. W. Kensler, I. Scholtus, K. K. Stephenson, P. Talalay, and A. Lozniewski Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors PNAS, May 28, 2002; 99(11): 7610 - 7615. [Abstract] [Full Text] [PDF]

				Y.-M. Yang, C. C. Conaway, J. W. Chiao, C.-X. Wang, S. Amin, J. Whysner, W. Dai, J. Reinhardt, and F.-L. Chung 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 Apoptosis Cancer Res., January 1, 2002; 62(1): 2 - 7. [Abstract] [Full Text] [PDF]

				E. Heiss, C. Herhaus, K. Klimo, H. Bartsch, and C. Gerhauser Nuclear Factor kappa B Is a Molecular Target for Sulforaphane-mediated Anti-inflammatory Mechanisms J. Biol. Chem., August 17, 2001; 276(34): 32008 - 32015. [Abstract] [Full Text] [PDF]

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