Neurochemical Research

, 35:152 | Cite as

Combination Treatment with Resveratrol and Sulforaphane Induces Apoptosis in Human U251 Glioma Cells

  • Hao JiangEmail author
  • Xia Shang
  • Hongtao Wu
  • Grace Huang
  • Yiyang Wang
  • Shaza Al-Holou
  • Subhash C. Gautam
  • Michael Chopp
Original Paper


Resveratrol is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Sulforaphane belongs to the family of isothiocyanates and is highly enriched in cruciferous vegetables. Our previous study showed that resveratrol, when used at high concentrations, inhibited cell proliferation, caused the cell cycle arrest and induced apoptotic cell death in glioma cells. In the current study, we tested the effect of combination treatment with resveratrol and sulforaphane, when both were used at low concentrations, on cell proliferation, migration and death in human U251 glioma cells. Our study shows that combination treatment with resveratrol and sulforaphane inhibits cell proliferation and migration, reduces cell viability, induces lactate dehydrogenase release, decreases pro-survival Akt phosphorylation and increases caspase-3 activation. The use of combination of bioactive food components, such as resveratrol and sulforaphane, may be a viable approach for the treatment of glioma.


Resveratrol Sulforaphane Glioma Apoptosis Caspase-3 Akt 



The study is supported in part by NIH grant R21 AT003463-01A2.


  1. 1.
    Koul D, Shen R, Bergh S et al (2006) Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther 5:637–644CrossRefPubMedGoogle Scholar
  2. 2.
    Boiardi A, Silvani A, Milanesi I et al (1991) Primary glial tumor patients treated by combining cis-platin and etoposide. J Neurooncol 11:165–170CrossRefPubMedGoogle Scholar
  3. 3.
    Kondo Y, Hollingsworth EF, Kondo S (2004) Molecular targeting for malignant gliomas (Review). Int J Oncol 24:1101–1109PubMedGoogle Scholar
  4. 4.
    Lambert JD, Hong J, Yang GY et al (2005) Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations. Am J Clin Nutr 81:284S–291SPubMedGoogle Scholar
  5. 5.
    Harikumar KB, Aggarwal BB (2008) Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 7:1020–1035PubMedGoogle Scholar
  6. 6.
    Delmas D, Lancon A, Colin D et al (2006) Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 7:423–442CrossRefPubMedGoogle Scholar
  7. 7.
    Kundu JK, Surh YJ (2008) Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett 269:243–261CrossRefPubMedGoogle Scholar
  8. 8.
    Tseng SH, Lin SM, Chen JC et al (2004) Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res 10:2190–2202CrossRefPubMedGoogle Scholar
  9. 9.
    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 89:2399–2403CrossRefPubMedGoogle Scholar
  10. 10.
    Matusheski NV, Jeffery EH (2001) Comparison of the bioactivity of two glucoraphanin hydrolysis products found in broccoli, sulforaphane and sulforaphane nitrile. J Agric Food Chem 49:5743–5749CrossRefPubMedGoogle Scholar
  11. 11.
    Myzak MC, Ho E, Dashwood RH (2006) Dietary agents as histone deacetylase inhibitors. Mol Carcinog 45:443–446CrossRefPubMedGoogle Scholar
  12. 12.
    Fimognari C, Hrelia P (2007) Sulforaphane as a promising molecule for fighting cancer. Mutat Res 635:90–104CrossRefPubMedGoogle Scholar
  13. 13.
    Karmakar S, Banik NL, Patel SJ et al (2006) Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cells. Neurosci Lett 407:53–58CrossRefPubMedGoogle Scholar
  14. 14.
    Jiang H, Zhang L, Kuo J et al (2005) Resveratrol-induced apoptotic death in human U251 glioma cells. Mol Cancer Ther 4:554–561CrossRefPubMedGoogle Scholar
  15. 15.
    Jiang H, Movsesyan V, Fink DW Jr et al (1997) Expression of human p140trk receptors in p140trk-deficient, PC12/endothelial cells results in nerve growth factor-induced signal transduction and DNA synthesis. J Cell Biochem 66:229–244CrossRefPubMedGoogle Scholar
  16. 16.
    Everitt AV, Hilmer SN, Brand-Miller JC et al (2006) Dietary approaches that delay age-related diseases. Clin Interv Aging 1:11–31CrossRefPubMedGoogle Scholar
  17. 17.
    Willett WC (1995) Diet, nutrition, and avoidable cancer. Environ Health Perspect 103(Suppl 8):165–170CrossRefPubMedGoogle Scholar
  18. 18.
    Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421CrossRefPubMedGoogle Scholar
  19. 19.
    Shimizu M, Shirakami Y, Sakai H et al (2007) EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett 262:10–18CrossRefGoogle Scholar
  20. 20.
    Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418CrossRefPubMedGoogle Scholar
  21. 21.
    Aziz MH, Kumar R, Ahmad N (2003) Cancer chemoprevention by resveratrol: in vitro and in vivo studies and the underlying mechanisms (review). Int J Oncol 23:17–28PubMedGoogle Scholar
  22. 22.
    Morris GZ, Williams RL, Elliott MS et al (2002) Resveratrol induces apoptosis in LNCaP cells and requires hydroxyl groups to decrease viability in LNCaP and DU 145 cells. Prostate 52:319–329CrossRefPubMedGoogle Scholar
  23. 23.
    Lin HY, Shih A, Davis FB et al (2002) Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. J Urol 168:748–755CrossRefPubMedGoogle Scholar
  24. 24.
    Joe AK, Liu H, Suzui M et al (2002) Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res 8:893–903PubMedGoogle Scholar
  25. 25.
    Park JW, Choi YJ, Suh SI et al (2001) Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity. Carcinogenesis 22:1633–1639CrossRefPubMedGoogle Scholar
  26. 26.
    Mouria M, Gukovskaya AS, Jung Y et al (2002) Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome C release and apoptosis. Int J Cancer 98:761–769CrossRefPubMedGoogle Scholar
  27. 27.
    Gao X, Xu YX, Divine G et al (2002) Disparate in vitro and in vivo antileukemic effects of resveratrol, a natural polyphenolic compound found in grapes. J Nutr 132:2076–2081PubMedGoogle Scholar
  28. 28.
    Wolter F, Akoglu B, Clausnitzer A et al (2001) Downregulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell cycle arrest in colon cancer cell lines. J Nutr 131:2197–2203PubMedGoogle Scholar
  29. 29.
    Zhang W, Fei Z, Zhen HN et al (2006) Resveratrol inhibits cell growth and induces apoptosis of rat C6 glioma cells. J Neurooncol 81:231–240CrossRefPubMedGoogle Scholar
  30. 30.
    Bertl E, Bartsch H, Gerhauser C (2006) Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol Cancer Ther 5:575–585CrossRefPubMedGoogle Scholar
  31. 31.
    Weisburger JH (1999) Carcinogenicity and mutagenicity testing, then and now. Mutat Res 437:105–112CrossRefPubMedGoogle Scholar
  32. 32.
    Choi WY, Choi BT, Lee WH, Choi YH (2008) Sulforaphane generates reactive oxygen species leading to mitochondrial perturbation for apoptosis in human leukemia U937 cells. Biomed PharmacotherGoogle Scholar
  33. 33.
    Park SY, Kim GY, Bae SJ et al (2007) Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3. Oncol Rep 18:181–187PubMedGoogle Scholar
  34. 34.
    Pledgie-Tracy A, Sobolewski MD, Davidson NE (2007) Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther 6:1013–1021CrossRefPubMedGoogle Scholar
  35. 35.
    Choi S, Singh SV (2005) Bax and Bak are required for apoptosis induction by sulforaphane, a cruciferous vegetable-derived cancer chemopreventive agent. Cancer Res 65:2035–2043CrossRefPubMedGoogle Scholar
  36. 36.
    Kim BR, Hu R, Keum YS et al (2003) Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. Cancer Res 63:7520–7525PubMedGoogle Scholar
  37. 37.
    Sexton E, Van Themsche C, LeBlanc K et al (2006) Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer 5:45CrossRefPubMedGoogle Scholar
  38. 38.
    Aziz MH, Nihal M, Fu VX et al (2006) Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3′-kinase/Akt pathway and Bcl-2 family proteins. Mol Cancer Ther 5:1335–1341CrossRefPubMedGoogle Scholar
  39. 39.
    Chaudhuri D, Orsulic S, Ashok BT (2007) Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells. Mol Cancer Ther 6:334–345CrossRefPubMedGoogle Scholar
  40. 40.
    Jin CY, Moon DO, Lee JD et al (2007) Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis through downregulation of ERK and Akt in lung adenocarcinoma A549 cells. Carcinogenesis 28:1058–1066CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Hao Jiang
    • 1
    Email author
  • Xia Shang
    • 1
  • Hongtao Wu
    • 2
  • Grace Huang
    • 1
  • Yiyang Wang
    • 1
  • Shaza Al-Holou
    • 1
  • Subhash C. Gautam
    • 3
  • Michael Chopp
    • 1
    • 4
  1. 1.Department of NeurologyHenry Ford HospitalDetroitUSA
  2. 2.Department of NeurosurgeryHenry Ford HospitalDetroitUSA
  3. 3.Department of SurgeryHenry Ford HospitalDetroitUSA
  4. 4.Department of PhysicsOakland UniversityRochester HillsUSA

Personalised recommendations