Abstract
Sulforaphane (SUL), one of the isothiocyanates (ITCs), has recently been focused due to its inhibitory effects on tumor cell growth in vitro and in vivo, which is dependent on the direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of SUL and its mechanism of action. Using the human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of SUL on the various steps of angiogenesis, including the proliferation of endothelial cells, tubular formation, and matrix metalloproteinase (MMP) production. Sulforaphane induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on cell apoptosis. Also SUL inhibited tube formation on matrigel, but did not affect MMP production. The present results demonstrate the anti-angiogenic activity of SUL and its potential use as an anti-cancer drug is suggested.
Similar content being viewed by others
Abbreviations
- aFGF:
-
Acidic fibroblast growth factor
- DMSO:
-
Dimethyl sulfoxide
- ECs:
-
Endothelial cells
- FCS:
-
Fetal calf serum
- HUVECs:
-
Human umbilical vein endothelial cells
- ITCs:
-
Isothiocyanates
- MMP:
-
Matrix metalloproteinase
- PBS:
-
Phosphate-buffered saline
- SUL:
-
Sulforaphane
- TUNEL:
-
Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling
References
Kohlmeier L, Mendez M (1997) Controversies surrounding diet and breast cancer. Proc Nutr Soc 56:369–382
Zhang SM, Hunter DJ, Rosner BA et al (2000) Intakes of fruits, vegetables, and related nutrients and the risk of non-Hodgkin’s lymphoma among women. Cancer Epidemiol Biomarkers Prev 9:477–485
Cohen JH, Kristal AR, Stanford JL (2000) Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst 92:61–68
Kolonel LN, Hankin JH, Whittemore AS et al (2000) Vegetables, fruits, legumes and prostate cancer: a multiethnic case–control study. Cancer Epidemiol Biomarkers Prev 9:795–804
Hecht SS (2000) Inhibition of carcinogenesis by isothiocyanates. Drug Metab Rev 32:395–411
Wattenberg LW (1987) Inhibitory effects of benzyl isothiocyanate administered shortly before diethylnitrosamine or benzo[a]pyrene on pulmonary and forestomach neoplasia in A/J mice. Carcinogenesis 8:1971–1973
Yang YM, Conaway CC, Chiao JW et al (2002) 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 62:2–7
Zhang Y, Kensler TW, Cho CG et al (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 91:3147–3150
Zhang Y, Talalay P (1998) Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes. Cancer Res 58:4632–4639
Prestera T, Talalay P (1995) Electrophile and antioxidant regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA 92:8965–8969
Ye L, Zhang Y (2001) Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes. Carcinogenesis 22:1987–1992
Fahey JW, Zalcmann AT, Talalay P (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56:5–51
Gao X, Dinkova-Kostova AT, Talalay P (2001) Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane. Proc Natl Acad Sci USA 98:15221–15226
Fahey JW, Zhang Y, Talalay P (1997) Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA 94:10367–10372
Zhang Y, Talalay P, Cho CG et al (1992) A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA 89:2399–2403
Fimognari C, Nusse M, Cesari R et al (2002) Growth inhibition, cell-cycle arrest and apoptosis in human T-cell leukemia by the isothiocyanate sulforaphane. Carcinogenesis 23:581–586
Gamet-Payrastre L, Li P, Lumeau S et al (2000) Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res 60:1426–1433
Singh SV, Herman-Antosiewicz A, Singh AV et al (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
Chiao JW, Chung FL, Kancherla R et al (2002) Sulforaphane and its metabolite mediate growth arrest and apoptosis in human prostate cancer cells. Int J Oncol 20:631–636
Bonnesen C, Eggleston IM, Hayes JD (2001) Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 61:6120–6130
Fimognari C, Nusse M, Berti F et al (2002) Cyclin D3 and p53 mediate sulforaphane-induced cell cycle delay and apoptosis in non-transformed human T lymphocytes. Cell Mol Life Sci 59:2004–2012
Yazawa K, Tsuno NH, Kitayama J et al (2005) Selective inhibition of cyclooxygenase (COX)-2 inhibits endothelial cell proliferation by induction of cell cycle arrest. Int J Cancer 113:541–548
Asakage M, Tsuno NH, Kitayama J et al (2004) 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on G1 cell cycle arrest. Anticancer Drugs 15:625–632
Tomozawa S, Nagawa H, Tsuno N et al (1999) Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522. Br J Cancer 81:1274–1279
Hecht SS (1999) Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J Nutr 129:768S-774S
Talalay P, Zhang Y (1996) Chemoprotection against cancer by isothiocyanates and glucosinolates. Biochem Soc Trans 24:806–810
Bertl E, Bartsch H, Gerhauser C (2006) Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol Cancer Ther 5:575–585
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312
Matsuda K, Yoshida K, Taya Y et al (2002) p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 62:2883–2889
Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family␣proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487
Kluck RM, Bossy-Wetzel E, Green DR et al (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136
Hanahan D (1997) Signaling vascular morphogenesis and maintenance. Science 277:48–50
Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31
Jiao D, Yu MC, Hankin JH et al (1998) Total isothiocyanate contents in cooked vegetables frequently consumed in Singapore. Journal of Agricultural and Food Chemistry 46:1055–1058
Ye L, Dinkova-Kostova AT, Wade KL et al (2002) Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta 316:43–53
Acknowledgements
This study was supported partly by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, partly by a grant from the Ministry of Health, Labour and Welfare of Japan, and partly by a grant from the Sankyo Foundation of Life Science.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Asakage, M., Tsuno, N.H., Kitayama, J. et al. Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis. Angiogenesis 9, 83–91 (2006). https://doi.org/10.1007/s10456-006-9034-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-006-9034-0