2,437
Views
113
CrossRef citations to date
0
Altmetric
Articles

Nrf2 targeting by sulforaphane: A potential therapy for cancer treatment

ORCID Icon, , , ORCID Icon, , , & show all

References

  • Abbas, A., Hall, J. A., Patterson, W. L., 3rd, Ho, E., Hsu, A., Al-Mulla, F. and Georgel, P. T. (2016). Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines. Biochem. Cell Biol. 94:71–81.
  • Alumkal, J. J., Slottke, R., Schwartzman, J., Cherala, G., Munar, M., Graff, J. N., Beer, T. M., Ryan, C. W., Koop, D. R., Gibbs, A., Gao, L., Flamiatos, J. F., Tucker, E., Kleinschmidt, R. and Mori, M. (2015). A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer. Invest. New Drugs 33:480–489.
  • Angelino, D. and Jeffery, E. (2014). Glucosinolate hydrolysis and bioavailability of resulting isothiocyanates: focus on glucoraphanin. J. Funct. Foods 7:67–76.
  • Ares, A. M., Valverde, S., Bernal, J. L., Nozal, M. J., and Bernal, J. (2015). Development and validation of a LC–MS/MS method to determine sulforaphane in honey. Food Chem. 181:263–269.
  • Asakage, M., Tsuno, N. H., Kitayama, J., Tsuchiya, T., Yoneyama, S., Yamada, J., Okaji, Y., Kaisaki, S., Osada, T., Takahashi, K. and Nagawa, H. (2006). Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis. Angiogenesis 9:83–91.
  • Atwell, L. L., Hsu, A., Wong, C. P., Stevens, J. F., Bella, D., Yu, T. W., Pereira, C. B., Löhr, C. V., Christensen, J. M. and Dashwood, R. H. (2015). Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase‐treated broccoli sprout extract. Mol. Nutr. Food Res. 59:424–433.
  • Atwell, L. L., Zhang, Z., Mori, M., Farris, P. E., Vetto, J. T., Naik, A. M., Oh, K. Y., Thuillier, P., Ho, E. and Shannon, J. (2015). Sulforaphane bioavailability and chemopreventive activity in women scheduled for breast biopsy. Cancer Prev. Res. (Phila) 8:1184–1191.
  • Bacon, J. R., Williamson, G., Garner, R. C., Lappin, G., Langouet, S. and Bao, Y. (2003). Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes. Carcinogenesis 24:1903–1911.
  • Bergantin, E., Quarta, C., Nanni, C., Fanti, S., Pession, A., Cantelli-Forti, G., Tonelli, R. and Hrelia, P. (2014). Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice. Cancer Biol. Ther. 15:1219–1225.
  • Bertl, E., Bartsch, H. and Gerhauser, C. (2006). Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol. Cancer Ther. 5:575–585.
  • Block, G., Patterson, B. and Subar, A. (1992). Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr. Cancer 18:1–29.
  • Block, K. I., Gyllenhaal, C., Lowe, L., Amedei, A., Amin, A. R., Amin, A., Aquilano, K., Arbiser, J., Arreola, A., Arzumanyan, A., Ashraf, S. S., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A., Bishayee, A., Blain, S. W., Block, P. B., Boosani, C. S., Carey, T. E., Carnero, A., Carotenuto, M., Casey, S. C., Chakrabarti, M., Chaturvedi, R., Chen, G. Z., Chen, H., Chen, S., Chen, Y. C., Choi, B. K., Ciriolo, M. R., Coley, H. M., Collins, A. R., Connell, M., Crawford, S., Curran, C. S., Dabrosin, C., Damia, G., Dasgupta, S., DeBerardinis, R. J., Decker, W. K., Dhawan, P., Diehl, A. M., Dong, J. T., Dou, Q. P., Drew, J. E., Elkord, E., El-Rayes, B., Feitelson, M. A., Felsher, D. W., Ferguson, L. R., Fimognari, C., Firestone, G. L., Frezza, C., Fujii, H., Fuster, M. M., Generali, D., Georgakilas, A. G., Gieseler, F., Gilbertson, M., Green, M. F., Grue, B., Guha, G., Halicka, D., Helferich, W. G., Heneberg, P., Hentosh, P., Hirschey, M. D., Hofseth, L. J., Holcombe, R. F., Honoki, K., Hsu, H. Y., Huang, G. S., Jensen, L. D., Jiang, W. G., Jones, L. W., Karpowicz, P. A., Keith, W. N., Kerkar, S. P., Khan, G. N., Khatami, M., Ko, Y. H., Kucuk, O., Kulathinal, R. J., Kumar, N. B., Kwon, B. S., Le, A., Lea, M. A., Lee, H. Y., Lichtor, T., Lin, L. T., Locasale, J. W., Lokeshwar, B. L., Longo, V. D., Lyssiotis, C. A., MacKenzie, K. L., Malhotra, M., Marino, M., Martinez-Chantar, M. L., Matheu, A., Maxwell, C., McDonnell, E., Meeker, A. K., Mehrmohamadi, M., Mehta, K., Michelotti, G. A., Mohammad, R. M., Mohammed, S. I., Morre, D. J., Muralidhar, V., Muqbil, I., Murphy, M. P., Nagaraju, G. P., Nahta, R., Niccolai, E., Nowsheen, S., Panis, C., Pantano, F., Parslow, V. R., Pawelec, G., Pedersen, P. L., Poore, B., Poudyal, D., Prakash, S., Prince, M., Raffaghello, L., Rathmell, J. C., Rathmell, W. K., Ray, S. K., Reichrath, J., Rezazadeh, S., Ribatti, D., Ricciardiello, L., Robey, R. B., Rodier, F., Rupasinghe, H. P., Russo, G. L., Ryan, E. P., Samadi, A. K., Sanchez-Garcia, I., Sanders, A. J., Santini, D., Sarkar, M., Sasada, T., Saxena, N. K., Shackelford, R. E., Shantha Kumara, H. M., Sharma, D., Shin, D. M., Sidransky, D., Siegelin, M. D., Signori, E., Singh, N., Sivanand, S., Sliva, D., Smythe, C., Spagnuolo, C., Stafforini, D. M., Stagg, J., Subbarayan, P. R., Sundin, T., Talib, W. H., Thompson, S. K., Tran, P. T., Ungefroren, H., Vander Heiden, M. G., Venkateswaran, V., Vinay, D. S., Vlachostergios, P. J., Wang, Z., Wellen, K. E., Whelan, R. L., Yang, E. S., Yang, H., Yang, X., Yaswen, P., Yedjou, C., Yin, X., Zhu, J. and Zollo, M. (2015). Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin. Cancer Biol. 35Suppl:S276–S304.
  • Budnowski, J., Hanschen, F. S., Lehmann, C., Haack, M., Brigelius-Flohé, R., Kroh, L. W., Blaut, M., Rohn, S. and Hanske, L. (2013). A derivatization method for the simultaneous detection of glucosinolates and isothiocyanates in biological samples. Anal. Biochem. 441:199–207.
  • Cabello-Hurtado, F., Gicquel, M. and Esnault, M.-A. (2012). Evaluation of the antioxidant potential of cauliflower (Brassica oleracea) from a glucosinolate content perspective. Food Chem. 132:1003–1009.
  • Chang, C. C., Hung, C. M., Yang, Y. R., Lee, M. J. and Hsu, Y. C. (2013). Sulforaphane induced cell cycle arrest in the G2/M phase via the blockade of cyclin B1/CDC2 in human ovarian cancer cells. J. Ovarian Res. 6:41.
  • Chartoumpekis, D. V., Wakabayashi, N. and Kensler, T. W. (2015). Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism. Biochem. Soc. Trans. 43:639–644.
  • Chorley, B. N., Campbell, M. R., Wang, X., Karaca, M., Sambandan, D., Bangura, F., Xue, P., Pi, J., Kleeberger, S. R. and Bell, D. A. (2012). Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 40:7416–7429.
  • Clarke, J. D., Dashwood, R. H. and Ho, E. (2008). Multi-targeted prevention of cancer by sulforaphane. Cancer Lett. 269:291–304.
  • Clarke, J. D., Hsu, A., Yu, Z., Dashwood, R. H. and Ho, E. (2011). Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells. Mol. Nutr. Food Res. 55:999–1009.
  • Conzatti, A., Fróes, F., Schweigert Perry, I. D. and Souza, C. (2014). Clinical and molecular evidence of the consumption of broccoli, glucoraphanin and sulforaphane in humans. Nutr. Hosp. 31:559–569.
  • Cornblatt, B. S., Ye, L., Dinkova-Kostova, A. T., Erb, M., Fahey, J. W., Singh, N. K., Chen, M. S., Stierer, T., Garrett-Mayer, E., Argani, P., Davidson, N. E., Talalay, P., Kensler, T. W. and Visvanathan, K. (2007). Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis 28:1485–1490.
  • Cornelis, M. C., El-Sohemy, A. and Campos, H. (2007). GSTT1 genotype modifies the association between cruciferous vegetable intake and the risk of myocardial infarction. Am. J. Clin. Nutr. 86:752–758.
  • Danilov, C. A., Chandrasekaran, K., Racz, J., Soane, L., Zielke, C. and Fiskum, G. (2009). Sulforaphane protects astrocytes against oxidative stress and delayed death caused by oxygen and glucose deprivation. Glia 57:645–656.
  • Davis, R., Singh, K. P., Kurzrock, R. and Shankar, S. (2009). Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors. Oncol. Rep. 22:1473–1478.
  • De Nicola, G. R., Rollin, P., Mazzon, E. and Iori, R. (2014). Novel gram-scale production of enantiopure R-sulforaphane from Tuscan black kale seeds. Molecules 19:6975–6986.
  • DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., Scrimieri, F., Winter, J. M., Hruban, R. H., Iacobuzio-Donahue, C., Kern, S. E., Blair, I. A. and Tuveson, D. A. (2011). Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–109.
  • Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M. and Talalay, P. (2002). Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 99:11908–11913.
  • Dodson, M., Redmann, M., Rajasekaran, N. S., Darley-Usmar, V. and Zhang, J. (2015). KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem. J. 469:347–355.
  • Egner, P. A., Chen, J. G., Wang, J. B., Wu, Y., Sun, Y., Lu, J. H., Zhu, J., Zhang, Y. H., Chen, Y. S. and Friesen, M. D. (2011). Bioavailability of sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prev. Res. 4:384–395.
  • Egner, P. A., Chen, J. G., Wang, J. B., Wu, Y., Sun, Y., Lu, J. H., Zhu, J., Zhang, Y. H., Chen, Y. S., Friesen, M. D., Jacobson, L. P., Munoz, A., Ng, D., Qian, G. S., Zhu, Y. R., Chen, T. Y., Botting, N. P., Zhang, Q., Fahey, J. W., Talalay, P., Groopman, J. D. and Kensler, T. W. (2011). Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prev. Res. 4:384–395.
  • Facchini, A., Stanic, I., Cetrullo, S., Borzì, R. M., Filardo, G. and Flamigni, F. (2011). Sulforaphane protects human chondrocytes against cell death induced by various stimuli. J. Cell. Physiol. 226:1771–1779.
  • Fahey, J. W., Stephenson, K. K., Dinkova-Kostova, A. T., Egner, P. A., Kensler, T. W. and Talalay, P. (2005). Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes. Carcinogenesis 26:1247–1255.
  • Fahey, J. W., Zhang, Y. and Talalay, P. (1997). Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl. Acad. Sci. U. S. A. 94:10367–10372.
  • Feskanich, D., Ziegler, R. G., Michaud, D. S., Giovannucci, E. L., Speizer, F. E., Willett, W. C. and Colditz, G. A. (2000). Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J. Natl. Cancer Inst. 92:1812–1823.
  • Fimognari, C., Turrini, E., Sestili, P., Calcabrini, C., Carulli, G., Fontanelli, G., Rousseau, M., Cantelli-Forti, G. and Hrelia, P. (2014). Antileukemic activity of sulforaphane in primary blasts from patients affected by myelo- and lympho-proliferative disorders and in hypoxic conditions. PLoS One 9:e101991.
  • Ganin, H., Rayo, J., Amara, N., Levy, N., Krief, P. and Meijler, M. M. (2013). Sulforaphane and erucin, natural isothiocyanates from broccoli, inhibit bacterial quorum sensing. Medchemcomm 4:175–179.
  • Gross-Steinmeyer, K., Stapleton, P. L., Tracy, J. H., Bammler, T. K., Strom, S. C. and Eaton, D. L. (2010). Sulforaphane- and phenethyl isothiocyanate-induced inhibition of aflatoxin B1-mediated genotoxicity in human hepatocytes: role of GSTM1 genotype and CYP3A4 gene expression. Toxicol. Sci. 116:422–432.
  • Han, D. and Row, K. H. (2011). Separation and purification of sulforaphane from broccoli by solid phase extraction. Int. J. Mol. Sci. 12:1854–1861.
  • Hanada, N., Takahata, T., Zhou, Q., Ye, X., Sun, R., Itoh, J., Ishiguro, A., Kijima, H., Mimura, J., Itoh, K., Fukuda, S. and Saijo, Y. (2012). Methylation of the KEAP1 gene promoter region in human colorectal cancer. BMC Cancer 12:66.
  • Hanahan, D. and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell 144:646–674.
  • Hayes, J. D. and Dinkova-Kostova, A. T. (2014). The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39:199–218.
  • Hong, F., Freeman, M. L. and Liebler, D. C. (2005). Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem. Res. Toxicol. 18:1917–1926.
  • Houghton, C. A., Fassett, R. G. and Coombes, J. S. (2016). Sulforaphane and other nutrigenomic Nrf2 activators: Can the clinician's expectation be matched by the reality?. Oxid. Med. Cell. Longev. 2016:17.
  • Hsu, Y. C., Chang, S. J., Wang, M. Y., Chen, Y. L. and Huang, T. Y. (2013). Growth inhibition and apoptosis of neuroblastoma cells through ROS-independent MEK/ERK activation by sulforaphane. Cell Biochem. Biophys. 66:765–774.
  • Huang, Y., Li, W., Su, Z. Y. and Kong, A. N. (2015). The complexity of the Nrf2 pathway: beyond the antioxidant response. J. Nutr. Biochem. 26:1401–1413.
  • Jackson, S. J., Singletary, K. W. and Venema, R. C. (2007). Sulforaphane suppresses angiogenesis and disrupts endothelial mitotic progression and microtubule polymerization. Vascul. Pharmacol. 46:77–84.
  • Jee, H. G., Lee, K. E., Kim, J. B., Shin, H. K. and Youn, Y. K. (2011). Sulforaphane inhibits oral carcinoma cell migration and invasion in vitro. Phytother. Res. 25:1623–1628.
  • Jo, G. H., Kim, G. Y., Kim, W. J., Park, K. Y. and Choi, Y. H. (2014). Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway. Int. J. Oncol. 45:1497–1506.
  • Joseph, M. A., Moysich, K. B., Freudenheim, J. L., Shields, P. G., Bowman, E. D., Zhang, Y., Marshall, J. R. and Ambrosone, C. B. (2004). Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk. Nutr. Cancer 50:206–213.
  • Joshipura, K. J., Ascherio, A., Manson, J. E., Stampfer, M. J., Rimm, E. B., Speizer, F. E., Hennekens, C. H., Spiegelman, D. and Willett, W. C. (1999). Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA 282:1233–1239.
  • Kallifatidis, G., Rausch, V., Baumann, B., Apel, A., Beckermann, B. M., Groth, A., Mattern, J., Li, Z., Kolb, A., Moldenhauer, G., Altevogt, P., Wirth, T., Werner, J., Schemmer, P., Buchler, M. W., Salnikov, A. V. and Herr, I. (2009). Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut 58:949–963.
  • Kanematsu, S., Yoshizawa, K., Uehara, N., Miki, H., Sasaki, T., Kuro, M., Lai, Y. C., Kimura, A., Yuri, T. and Tsubura, A. (2011). Sulforaphane inhibits the growth of KPL-1 human breast cancer cells in vitro and suppresses the growth and metastasis of orthotopically transplanted KPL-1 cells in female athymic mice. Oncol. Rep. 26:603–608.
  • Karin, M. and Dhar, D. (2016). Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis 37:541–546.
  • Kensler, T. W., Chen, J. G., Egner, P. A., Fahey, J. W., Jacobson, L. P., Stephenson, K. K., Ye, L., Coady, J. L., Wang, J. B., Wu, Y., Sun, Y., Zhang, Q. N., Zhang, B. C., Zhu, Y. R., Qian, G. S., Carmella, S. G., Hecht, S. S., Benning, L., Gange, S. J., Groopman, J. D. and Talalay, P. (2005). Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthrene tetraols in a randomized clinical trial in He Zuo township, Qidong, People's Republic of China. Cancer Epidemiol., Biomarkers Prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 14:2605–2613.
  • Kensler, T. W., Egner, P. A., Agyeman, A. S., Visvanathan, K., Groopman, J. D., Chen, J. G., Chen, T. Y., Fahey, J. W. and Talalay, P. (2013). Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top. Curr. Chem. 329:163–177.
  • Kensler, T. W. and Wakabayashi, N. (2010). Nrf2: friend or foe for chemoprevention? Carcinogenesis 31:90–99.
  • Keum, Y. S. (2011). Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications. Ann. N. Y. Acad. Sci. 1229:184–189.
  • Key, T. (2011). Fruit and vegetables and cancer risk. Br. J. Cancer 104:6–11.
  • Kim, D. H., Sung, B., Kang, Y. J., Hwang, S. Y., Kim, M. J., Yoon, J. H., Im, E. and Kim, N. D. (2015). Sulforaphane inhibits hypoxia-induced HIF-1alpha and VEGF expression and migration of human colon cancer cells. Int. J. Oncol. 47:2226–2232.
  • Kim, J. and Keum, Y. S. (2016). NRF2, a Key Regulator of Antioxidants with Two Faces towards Cancer. Oxid. Med. Cell. Longev. 2016:2746457.
  • Kim, M. R., Zhou, L., Park, B. H. and Kim, J. R. (2011). Induction of G(2)/M arrest and apoptosis by sulforaphane in human osteosarcoma U2-OS cells. Mol. Med. Rep. 4:929–934.
  • Knatko, E. V., Ibbotson, S. H., Zhang, Y., Higgins, M., Fahey, J. W., Talalay, P., Dawe, R. S., Ferguson, J., Huang, J. T., Clarke, R., Zheng, S., Saito, A., Kalra, S., Benedict, A. L., Honda, T., Proby, C. M. and Dinkova-Kostova, A. T. (2015). Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans. Cancer Prev. Res. (Phila) 8:475–486.
  • Ko, J.-Y., Choi, Y.-J., Jeong, G.-J. and Im, G.-I. (2013). Sulforaphane–PLGA microspheres for the intra-articular treatment of osteoarthritis. Biomaterials 34:5359–5368.
  • Kraft, A. D., Johnson, D. A. and Johnson, J. A. (2004). Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J. Neurosci. 24:1101–1112.
  • Lan, F., Pan, Q., Yu, H. and Yue, X. (2015). Sulforaphane enhances temozolomide-induced apoptosis because of down-regulation of miR-21 via Wnt/beta-catenin signaling in glioblastoma. J. Neurochem. 134:811–818.
  • Lau, A., Wang, X. J., Zhao, F., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E. and Zhang, D. D. (2010). A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30:3275–3285.
  • Lau, A., Zheng, Y., Tao, S., Wang, H., Whitman, S. A., White, E. and Zhang, D. D. (2013). Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner. Mol. Cell. Biol. 33:2436–2446.
  • Lee, C. S., Cho, H. J., Jeong, Y. J., Shin, J. M., Park, K. K., Park, Y. Y., Bae, Y. S., Chung, I. K., Kim, M., Kim, C. H., Jin, F., Chang, H. W. and Chang, Y. C. (2015). Isothiocyanates inhibit the invasion and migration of C6 glioma cells by blocking FAK/JNK-mediated MMP-9 expression. Oncol. Rep. 34:2901–2908.
  • Lee, Y. R., Noh, E. M., Han, J. H., Kim, J. M., Hwang, B. M., Kim, B. S., Lee, S. H., Jung, S. H., Youn, H. J., Chung, E. Y. and Kim, J. S. (2013). Sulforaphane controls TPA-induced MMP-9 expression through the NF-kappaB signaling pathway, but not AP-1, in MCF-7 breast cancer cells. BMB Rep. 46:201–206.
  • Lenzi, M., Fimognari, C. and Hrelia, P. (2014). Sulforaphane as a promising molecule for fighting cancer. Cancer Treat. Res. 159:207–223.
  • Li, Q., Xia, J., Yao, Y., Gong, D. W., Shi, H. and Zhou, Q. (2013). Sulforaphane inhibits mammary adipogenesis by targeting adipose mesenchymal stem cells. Breast Cancer Res. Treat. 141:317–324.
  • Li, Z., Liu, Y., Fang, Z., Yang, L., Zhuang, M., Zhang, Y., Zhao, W. and Sun, P. (2014). Variation of sulforaphane levels in broccoli (Brassica oleracea var. italica) during flower development and the role of gene AOP2. J. Liq. Chromatogr. Rel. Technol. 37:1199–1211.
  • Liang, H., Li, C., Yuan, Q. and Vriesekoop, F. (2008). Application of high-speed countercurrent chromatography for the isolation of sulforaphane from broccoli seed meal. J. Agric. Food. Chem. 56:7746–7749.
  • Lin, L. C., Yeh, C. T., Kuo, C. C., Lee, C. M., Yen, G. C., Wang, L. S., Wu, C. H., Yang, W. C. and Wu, A. T. (2012). Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/beta-catenin function. J. Agric. Food Chem. 60:7031–7039.
  • Liu, M., Yao, X. D., Li, W., Geng, J., Yan, Y., Che, J. P., Xu, Y. F. and Zheng, J. H. (2015). Nrf2 sensitizes prostate cancer cells to radiation via decreasing basal ROS levels. Biofactors 41:52–57.
  • Liu, Y., Kern, J. T., Walker, J. R., Johnson, J. A., Schultz, P. G. and Luesch, H. (2007). A genomic screen for activators of the antioxidant response element. Proc. Natl. Acad. Sci. U. S. A. 104:5205–5210.
  • López‐Cervantes, J., Tirado‐Noriega, L. G., Sánchez‐Machado, D. I., Campas‐Baypoli, O. N., Cantú‐Soto, E. U. and Núñez‐Gastélum, J. A. (2013). Biochemical composition of broccoli seeds and sprouts at different stages of seedling development. Int. J. Food Sci. Tech. 48:2267–2275.
  • Lozanovski, V. J., Houben, P., Hinz, U., Hackert, T., Herr, I. and Schemmer, P. (2014). Pilot study evaluating broccoli sprouts in advanced pancreatic cancer (POUDER trial) - study protocol for a randomized controlled trial. Trials 15:204.
  • Maheo, K., Morel, F., Langouet, S., Kramer, H., Le Ferrec, E., Ketterer, B. and Guillouzo, A. (1997). Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res. 57:3649–3652.
  • Manchali, S., Murthy, K. N. C. and Patil, B. S. (2012). Crucial facts about health benefits of popular cruciferous vegetables. J. Funct. Foods 4:94–106.
  • Matile, P. (1980). The mustard oil bomb-compartmentation of the myrosinase system. Biochem. Physiol. Pflanz. 175:722–731.
  • Meeran, S. M., Patel, S. N. and Tollefsbol, T. O. (2010). Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS One 5:e11457.
  • Menegon, S., Columbano, A. and Giordano, S. (2016). The Dual Roles of NRF2 in Cancer. Trends Mol. Med. 22:578–593.
  • Mirmiran, P., Noori, N., Zavareh, M. B. and Azizi, F. (2009). Fruit and vegetable consumption and risk factors for cardiovascular disease. Metabolism 58:460–468.
  • Moi, P., Chan, K., Asunis, I., Cao, A. and Kan, Y. W. (1994). Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc. Natl. Acad. Sci. U. S. A. 91:9926–9930.
  • Mondal, A., Biswas, R., Rhee, Y. H., Kim, J. and Ahn, J. C. (2016). Sulforaphene promotes Bax/Bcl2, MAPK-dependent human gastric cancer AGS cells apoptosis and inhibits migration via EGFR, p-ERK1/2 down-regulation. Gen. Physiol. Biophys. 35:25–34.
  • Moon, D. O., Kang, S. H., Kim, K. C., Kim, M. O., Choi, Y. H. and Kim, G. Y. (2010). Sulforaphane decreases viability and telomerase activity in hepatocellular carcinoma Hep3B cells through the reactive oxygen species-dependent pathway. Cancer Lett. 295:260–266.
  • Muller, T. and Hengstermann, A. (2012). Nrf2: friend and foe in preventing cigarette smoking-dependent lung disease. Chem. Res. Toxicol. 25:1805–1824.
  • Myzak, M. C., Karplus, P. A., Chung, F.-L. and Dashwood, R. H. (2004). A novel mechanism of chemoprotection by sulforaphane inhibition of histone deacetylase. Cancer Res. 64:5767–5774.
  • Myzak, M. C., Karplus, P. A., Chung, F. L. and Dashwood, R. H. (2004). A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res. 64:5767–5774.
  • Neuhouser, M. L., Patterson, R. E., Thornquist, M. D., Omenn, G. S., King, I. B. and Goodman, G. E. (2003). Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the β-carotene and retinol efficacy trial (CARET). Cancer Epidemiol. Biomarkers Prev. 12:350–358.
  • Nian, H., Delage, B., Ho, E. and Dashwood, R. H. (2009). Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds. Environ. Mol. Mutagen. 50:213–221.
  • Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., Shibata, T., Yamamoto, M. and Hirohashi, S. (2008). Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 68:1303–1309.
  • Pan, H., He, M., Liu, R., Brecha, N. C., Yu, A. C. and Pu, M. (2014). Sulforaphane protects rodent retinas against ischemia-reperfusion injury through the activation of the Nrf2/HO-1 antioxidant pathway. PLoS One 9:e114186.
  • Park, S. Y., Kim, G. Y., Bae, S. J., Yoo, Y. H. and Choi, Y. H. (2007). Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3. Oncol. Rep. 18:181–187.
  • Parnaud, G., Li, P., Cassar, G., Rouimi, P., Tulliez, J., Combaret, L. and Gamet-Payrastre, L. (2004). Mechanism of sulforaphane-induced cell cycle arrest and apoptosis in human colon cancer cells. Nutr. Cancer 48:198–206.
  • Pastorek, M., Simko, V., Takacova, M., Barathova, M., Bartosova, M., Hunakova, L., Sedlakova, O., Hudecova, S., Krizanova, O., Dequiedt, F., Pastorekova, S. and Sedlak, J. (2015). Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy. Int. J. Oncol. 47:51–60.
  • Pawlik, A., Wiczk, A., Kaczynska, A., Antosiewicz, J. and Herman-Antosiewicz, A. (2013). Sulforaphane inhibits growth of phenotypically different breast cancer cells. Eur. J. Nutr. 52:1949–1958.
  • Peng, X., Zhou, Y., Tian, H., Yang, G., Li, C., Geng, Y., Wu, S. and Wu, W. (2015). Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells. Oncol. Rep. 34:1565–1572.
  • Piberger, A. L., Keil, C., Platz, S., Rohn, S. and Hartwig, A. (2015). Sulforaphane inhibits damage-induced poly (ADP-ribosyl)ation via direct interaction of its cellular metabolites with PARP-1. Mol. Nutr. Food Res. 59:2231–2242.
  • Piberger, A. L., Koberle, B. and Hartwig, A. (2014). The broccoli-born isothiocyanate sulforaphane impairs nucleotide excision repair: XPA as one potential target. Arch. Toxicol. 88:647–658.
  • Pradhan, S. J., Mishra, R., Sharma, P. and Kundu, G. C. (2010). Quercetin and sulforaphane in combination suppress the progression of melanoma through the down-regulation of matrix metalloproteinase-9. Exp. Ther. Med. 1:915–920.
  • Rajendran, P., Kidane, A. I., Yu, T. W., Dashwood, W. M., Bisson, W. H., Lohr, C. V., Ho, E., Williams, D. E. and Dashwood, R. H. (2013). HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics 8:612–623.
  • Rausch, V., Liu, L., Kallifatidis, G., Baumann, B., Mattern, J., Gladkich, J., Wirth, T., Schemmer, P., Buchler, M. W., Zoller, M., Salnikov, A. V. and Herr, I. (2010). Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics. Cancer Res. 70:5004–5013.
  • Razis, A., Faizal, A., Iori, R. and Ioannides, C. (2011). The natural chemopreventive phytochemical R‐sulforaphane is a far more potent inducer of the carcinogen‐detoxifying enzyme systems in rat liver and lung than the S‐isomer. Int. J. Cancer 128:2775–2782.
  • Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S. and Foiani, M. (2011). HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature 471:74–79.
  • Roy, S. K., Srivastava, R. K. and Shankar, S. (2010). Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J. Mol. Signal. 5:10.
  • Rushmore, T. H. and Kong, A. N. (2002). Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr. Drug Metab. 3:481–490.
  • Russo, G. L. (2007). Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem. Pharmacol. 74:533–544.
  • Russo, M., Spagnuolo, C., Tedesco, I. and Russo, G. L. (2010). Phytochemicals in cancer prevention and therapy: truth or dare? Toxins (Basel) 2:517–551.
  • Sasaki, H., Suzuki, A., Shitara, M., Hikosaka, Y., Okuda, K., Moriyama, S., Yano, M. and Fujii, Y. (2013). Genotype analysis of the NRF2 gene mutation in lung cancer. Int. J. Mol. Med. 31:1135–1138.
  • Satoh, H., Moriguchi, T., Takai, J., Ebina, M. and Yamamoto, M. (2013). Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 73:4158–4168.
  • Shan, Y., Sun, C., Zhao, X., Wu, K., Cassidy, A. and Bao, Y. (2006). Effect of sulforaphane on cell growth, G(0)/G(1) phase cell progression and apoptosis in human bladder cancer T24 cells. Int. J. Oncol. 29:883–888.
  • Shan, Y., Wang, X., Wang, W., He, C. and Bao, Y. (2010). p38 MAPK plays a distinct role in sulforaphane-induced up-regulation of ARE-dependent enzymes and down-regulation of COX-2 in human bladder cancer cells. Oncol. Rep. 23:1133–1138.
  • Shen, G., Xu, C., Chen, C., Hebbar, V. and Kong, A. N. (2006). p53-independent G1 cell cycle arrest of human colon carcinoma cells HT-29 by sulforaphane is associated with induction of p21CIP1 and inhibition of expression of cyclin D1. Cancer Chemother. Pharmacol. 57:317–327.
  • Singh, S. V., Herman-Antosiewicz, A., Singh, A. V., Lew, K. L., Srivastava, S. K., Kamath, R., Brown, K. D., Zhang, L. and Baskaran, R. (2004). Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J. Biol. Chem. 279:25813–25822.
  • Singletary, K. and MacDonald, C. (2000). Inhibition of benzo[a]pyrene- and 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells bydibenzoylmethane and sulforaphane. Cancer Lett. 155:47–54.
  • Skupinska, K., Misiewicz-Krzeminska, I., Stypulkowski, R., Lubelska, K. and Kasprzycka-Guttman, T. (2009). Sulforaphane and its analogues inhibit CYP1A1 and CYP1A2 activity induced by benzo[a]pyrene. J. Biochem. Mol. Toxicol. 23:18–28.
  • Solis, L. M., Behrens, C., Dong, W., Suraokar, M., Ozburn, N. C., Moran, C. A., Corvalan, A. H., Biswal, S., Swisher, S. G., Bekele, B. N., Minna, J. D., Stewart, D. J. and Wistuba, I. I. (2010). Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin. Cancer Res. 16:3743–3753.
  • Sporn, M. B. (1991). Carcinogenesis and cancer: different perspectives on the same disease. Cancer Res. 51:6215–6218.
  • Sporn, M. B. and Suh, N. (2002). Chemoprevention: an essential approach to controlling cancer. Nature Rev. Cancer 2:537–543.
  • Sun, C. C., Li, S. J., Yang, C. L., Xue, R. L., Xi, Y. Y., Wang, L., Zhao, Q. L. and Li, D. J. (2015). Sulforaphane attenuates muscle inflammation in dystrophin-deficient mdx mice via NF-E2-related factor 2 (Nrf2)-mediated inhibition of NF-kappaB signaling pathway. J. Biol. Chem. 290:17784–17795.
  • Tang, L. and Zhang, Y. (2004). Dietary isothiocyanates inhibit the growth of human bladder carcinoma cells. J. Nutr. 134:2004–2010.
  • Tarozzi, A., Angeloni, C., Malaguti, M., Morroni, F., Hrelia, S. and Hrelia, P. (2013). Sulforaphane as a potential protective phytochemical against neurodegenerative diseases. Oxid. Med. Cell. Longev. 2013.
  • Thejass, P. and Kuttan, G. (2007). Modulation of cell-mediated immune response in B16F-10 melanoma-induced metastatic tumor-bearing C57BL/6 mice by sulforaphane. Immunopharmacol. Immunotoxicol. 29:173–186.
  • Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M. and Biswal, S. (2002). Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 62:5196–5203.
  • Tope, A. M. and Rogers, P. F. (2009). Evaluation of protective effects of sulforaphane on DNA damage caused by exposure to low levels of pesticide mixture using comet assay. J. Environ. Sci. Health. B. 44:657–662.
  • Tortorella, S. M., Royce, S. G., Licciardi, P. V. and Karagiannis, T. C. (2015). Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition. Antioxid. Redox Signal 22:1382–1424.
  • Verhoeven, D. T., Goldbohm, R. A., van Poppel, G., Verhagen, H. and van den Brandt, P. A. (1996). Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol. Biomarkers Prev. 5:733–748.
  • Vermeulen, M., Klopping-Ketelaars, I. W., van den Berg, R. and Vaes, W. H. (2008). Bioavailability and kinetics of sulforaphane in humans after consumption of cooked versus raw broccoli. J. Agric. Food. Chem. 56:10505–10509.
  • Vermeulen, M., Klöpping-Ketelaars, I. W., van den Berg, R. and Vaes, W. H. (2008). Bioavailability and kinetics of sulforaphane in humans after consumption of cooked versus raw broccoli. J. Agric. Food. Chem. 56:10505–10509.
  • Voorrips, L., Goldbohm, R., van Poppel, G., Sturmans, F., Hermus, R. and Van Den Brandt, P. (2000). Vegetable and fruit consumption and risks of colon and rectal cancer in a prospective cohort study The Netherlands Cohort Study on Diet and Cancer. Am. J. Epidemiol. 152:1081–1092.
  • Wang, G. C., Farnham, M. and Jeffery, E. H. (2012). Impact of thermal processing on sulforaphane yield from broccoli (Brassica oleracea L. ssp. italica). J. Agric. Food. Chem. 60:6743–6748.
  • Wang, H., Khor, T. O., Yang, Q., Huang, Y., Wu, T. Y., Saw, C. L., Lin, W., Androulakis, I. P. and Kong, A. N. (2012). Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes. Mol. Pharm. 9:2819–2827.
  • Wang, X. J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., Wong, P. K. and Zhang, D. D. (2008). Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235–1243.
  • Warburg, O. (1956). On respiratory impairment in cancer cells. Science 124:269–270.
  • Wright, W. E. and Shay, J. W. (2005). Telomere biology in aging and cancer. J. Am. Geriatr. Soc. 53:S292–294.
  • Wu, S., Powers, S., Zhu, W. and Hannun, Y. A. (2016). Substantial contribution of extrinsic risk factors to cancer development. Nature 529:43–47.
  • Xiang, M., Namani, A., Wu, S. and Wang, X. (2014). Nrf2: bane or blessing in cancer? J. Cancer Res. Clin. Oncol. 140:1251–1259.
  • Xu, C., Shen, G., Yuan, X., Kim, J. H., Gopalkrishnan, A., Keum, Y. S., Nair, S. and Kong, A. N. (2006). 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 27:437–445.
  • Xue, M., Qian, Q., Adaikalakoteswari, A., Rabbani, N., Babaei-Jadidi, R. and Thornalley, P. J. (2008). Activation of NF-E2–related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 57:2809–2817.
  • Yao, H., Wang, H., Zhang, Z., Jiang, B. H., Luo, J. and Shi, X. (2008). Sulforaphane inhibited expression of hypoxia-inducible factor-1alpha in human tongue squamous cancer cells and prostate cancer cells. Int. J. Cancer 123:1255–1261.
  • Yates, M. S., Tran, Q. T., Dolan, P. M., Osburn, W. O., Shin, S., McCulloch, C. C., Silkworth, J. B., Taguchi, K., Yamamoto, M., Williams, C. R., Liby, K. T., Sporn, M. B., Sutter, T. R. and Kensler, T. W. (2009). Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30:1024–1031.
  • Yoo, S. H., Lim, Y., Kim, S. J., Yoo, K. D., Yoo, H. S., Hong, J. T., Lee, M. Y. and Yun, Y. P. (2013). Sulforaphane inhibits PDGF-induced proliferation of rat aortic vascular smooth muscle cell by up-regulation of p53 leading to G1/S cell cycle arrest. Vascul. Pharmacol. 59:44–51.
  • Zhang, J., Walsh, M. F., Wu, G., Edmonson, M. N., Gruber, T. A., Easton, J., Hedges, D., Ma, X., Zhou, X., Yergeau, D. A., Wilkinson, M. R., Vadodaria, B., Chen, X., McGee, R. B., Hines-Dowell, S., Nuccio, R., Quinn, E., Shurtleff, S. A., Rusch, M., Patel, A., Becksfort, J. B., Wang, S., Weaver, M. S., Ding, L., Mardis, E. R., Wilson, R. K., Gajjar, A., Ellison, D. W., Pappo, A. S., Pui, C. H., Nichols, K. E. and Downing, J. R. (2015). Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373:2336–2346.
  • Zhang, Z., Wang, S., Zhou, S., Yan, X., Wang, Y., Chen, J., Mellen, N., Kong, M., Gu, J. and Tan, Y. (2014). Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. J. Mol. Cell. Cardiol. 77:42–52.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.