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Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells

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Abstract

Objectives

Resveratrol (RV), a natural polyphenol derived from red wine, recently showed the potential of anticancer and radiosensitizing effects. A recent study has suggested that the cancer stem cells (CSCs) may reflect the clinical refractory malignancy of brain tumors, including medulloblastoma (MB). The aim of the present study is to investigate the possible role of RV in radiosensitivity of MB cells and MB-associated CSCs.

Materials and methods

MB-associated CSCs were isolated and cultured by serum-free medium with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). The parental MB cells and MB-CSCs were treated with RV in different concentrations and assessed for cell viability. The treatment includes RV alone, radiation alone, or radiation combined with RV.

Results

MB-CSCs selected by serum-free medium with bFGF and EGF can form 3D spheroid formation and display enhanced self-renewal and highly co-expressed “stem cell” genes (Oct-4, Nanog, Nestin, and Musashi-1) as well as antiapoptotic genes (Bcl-2 and Bcl-xL). These MB-CSCs showed significant resistance to radiotherapy as compared to the parental MB cells. Importantly, 100 μM RV could effectively inhibit the proliferation of MB-CSCs and significantly enhance the radiosensitivity in RV-treated MB-CSCs.

Conclusions

Our data suggest that RV can effectively inhibit the proliferation and tumorigenicity of MB-CSCs and significantly synergistically enhance radiosensitivity in RV-treated MB-CSCs.

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References

  1. Atten MJ, Godoy-Romero E, Attar BM, Milson T, Zopel M, Holian O (2005) Resveratrol regulates cellular PKC alpha and delta to inhibit growth and induce apoptosis in gastric cancer cells. Invest New Drugs 23:111–119

    Article  PubMed  CAS  Google Scholar 

  2. Baatout S, Derradji H, Jacquet P, Ooms D, Michaux A, Mergeay M (2004) Enhanced radiation-induced apoptosis of cancer cell lines after treatment with resveratrol. Int J Mol Med 13:895–902

    PubMed  CAS  Google Scholar 

  3. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760

    Article  PubMed  CAS  Google Scholar 

  4. Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, Bogdahn U, Beier CP (2008) CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol 18:370–377

    Article  PubMed  Google Scholar 

  5. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507

    Article  PubMed  CAS  Google Scholar 

  6. Bradamante S, Barenghi L, Villa A (2004) Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 22:169–188

    PubMed  CAS  Google Scholar 

  7. Cervoni L, Cantore G (1995) Medulloblastoma in pediatric age: a single-institution review of prognostic factors. Childs Nerv Syst 11:80–84, discussion 85

    Article  PubMed  CAS  Google Scholar 

  8. Chakraborty PK, Mustafi SB, Ganguly S, Chatterjee M, Raha S (2008) Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia) cells by targeting a key survival protein, heat shock protein 70. Cancer Sci 99:1109–1116

    Article  PubMed  CAS  Google Scholar 

  9. Chiou SH, Ku HH, Tsai TH, Lin HL, Chen LH, Chien CS, Ho LL, Lee CH, Chang YL (2006) Moclobemide upregulated Bcl-2 expression and induced neural stem cell differentiation into serotonergic neuron via extracellular-regulated kinase pathway. Br J Pharmacol 148:587–598

    Article  PubMed  CAS  Google Scholar 

  10. Chiou SH, Kao CL, Chen YW, Chien CS, Hung SC, Lo JF, Chen YJ, Ku HH, Hsu MT, Wong TT (2008) Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor. PLoS ONE 3:e2090

    Article  PubMed  Google Scholar 

  11. Chiou SH, Yu CC, Huang CY, Lin SC, Liu CJ, Tsai TH, Chou SH, Chien CS, Ku HH, Lo JF (2008) Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14:4085–4095

    Article  PubMed  CAS  Google Scholar 

  12. Costea DE, Tsinkalovsky O, Vintermyr OK, Johannessen AC, Mackenzie IC (2006) Cancer stem cells—new and potentially important targets for the therapy of oral squamous cell carcinoma. Oral Dis 12:443–454

    Article  PubMed  CAS  Google Scholar 

  13. Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284

    Article  PubMed  CAS  Google Scholar 

  14. Das S, Das DK (2007) Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets 6:168–173

    Article  PubMed  CAS  Google Scholar 

  15. de la Lastra CA, Villegas I (2005) Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 49:405–430

    Article  PubMed  Google Scholar 

  16. Dennis M, Spiegler BJ, Hetherington CR, Greenberg ML (1996) Neuropsychological sequelae of the treatment of children with medulloblastoma. J Neurooncol 29:91–101

    Article  PubMed  CAS  Google Scholar 

  17. Ezeh UI, Turek PJ, Reijo RA, Clark AT (2005) Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104:2255–2265

    Article  PubMed  CAS  Google Scholar 

  18. Fong SP, Tsang KS, Chan AB, Lu G, Poon WS, Li K, Baum LW, Ng HK (2007) Tropism of neural progenitor cells to embryonic stem cells: neural induction and transplantation in a mouse ischemic stroke model. J Neurosci Res 85:1851–1862

    Article  PubMed  CAS  Google Scholar 

  19. Habrand JL, De Crevoisier R (2001) Radiation therapy in the management of childhood brain tumors. Childs Nerv Syst 17:121–133

    Article  PubMed  CAS  Google Scholar 

  20. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183

    Article  PubMed  CAS  Google Scholar 

  21. Hoppe-Hirsch E, Brunet L, Laroussinie F, Cinalli G, Pierre-Kahn A, Renier D, Sainte-Rose C, Hirsch JF (1995) Intellectual outcome in children with malignant tumors of the posterior fossa: influence of the field of irradiation and quality of surgery. Childs Nerv Syst 11:340–345, discussion 345–346

    Article  PubMed  CAS  Google Scholar 

  22. Ivanov VN, Partridge MA, Johnson GE, Huang SX, Zhou H, Hei TK (2008) Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. Exp Cell Res 314:1163–1176

    Article  PubMed  CAS  Google Scholar 

  23. Johnson GE, Ivanov VN, Hei TK (2008) Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival. Apoptosis 13:790–802

    Article  PubMed  CAS  Google Scholar 

  24. Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261

    Article  PubMed  CAS  Google Scholar 

  25. Kao CL, Chiou SH, Chen YJ, Singh S, Lin HT, Liu RS, Lo CW, Yang CC, Chi CW, Lee CH, Wong TT (2005) Increased expression of osteopontin gene in atypical teratoid/rhabdoid tumor of the central nervous system. Mod Pathol 18:769–778

    Article  PubMed  CAS  Google Scholar 

  26. Kuo PL, Chiang LC, Lin CC (2002) Resveratrol-induced apoptosis is mediated by p53-dependent pathway in Hep G2 cells. Life Sci 72:23–34

    Article  PubMed  CAS  Google Scholar 

  27. Liao HF, Kuo CD, Yang YC, Lin CP, Tai HC, Chen YY, Chen YJ (2005) Resveratrol enhances radiosensitivity of human non-small cell lung cancer NCI-H838 cells accompanied by inhibition of nuclear factor-kappa B activation. J Radiat Res (Tokyo) 46:387–393

    Article  CAS  Google Scholar 

  28. Neuzil J, Stantic M, Zobalova R, Chladova J, Wang X, Prochazka L, Dong L, Andera L, Ralph SJ (2007) Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: what’s in the name? Biochem Biophys Res Commun 355:855–859

    Article  PubMed  CAS  Google Scholar 

  29. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115

    Article  PubMed  CAS  Google Scholar 

  30. Roccaro AM, Leleu X, Sacco A, Moreau AS, Hatjiharissi E, Jia X, Xu L, Ciccarelli B, Patterson CJ, Ngo HT, Russo D, Vacca A, Dammacco F, Anderson KC, Ghobrial IM, Treon SP (2008) Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenstrom’s macroglobulinemia. Clin Cancer Res 14:1849–1858

    Article  PubMed  CAS  Google Scholar 

  31. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  32. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768

    Article  PubMed  CAS  Google Scholar 

  33. Whelan HT, Krouwer HG, Schmidt MH, Reichert KW, Kovnar EH (1998) Current therapy and new perspectives in the treatment of medulloblastoma. Pediatr Neurol 18:103–115

    Article  PubMed  CAS  Google Scholar 

  34. Yu LJ, Wu ML, Li H, Chen XY, Wang Q, Sun Y, Kong QY, Liu J (2008) Inhibition of STAT3 expression and signaling in resveratrol-differentiated medulloblastoma cells. Neoplasia 10:736–744

    Article  PubMed  CAS  Google Scholar 

  35. Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by research grants from NSC-(97-3111-B-075-001-MY3), Taipei Veterans General Hospital (V97E1-008, ER2-018, ER3-005, F-001), Taipei City Hospital (96002-62-092 and 97001-62-015), and National Yang-Ming University (Ministry of Education, Aim for the Top University Plan).

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Authors and Affiliations

  1. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan

    Kai-Hsi Lu & Chi-Hung Lin

  2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Yi-Wei Chen, Yi-Yen Lee, Chih-Yao Chiang, Chung-Lan Kao, Shih-Hwa Chiou & Yann-Jang Chen

  3. Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan

    Hung-Hai Ku

  4. Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan

    Yann-Jang Chen

  5. Department of Pediatric, Taipei City Hospital, Renai Branch, Taipei, Taiwan

    Yi-Yen Lee, Chih-Yao Chiang, Hung-Hai Ku & Yann-Jang Chen

  6. Department of Education and Research, Taipei Veterans General Hospital, Taipei, Taiwan

    Ping-Hsing Tsai, Ming-Long Tsai & Shih-Hwa Chiou

  7. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Yi-Wei Chen

  8. Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan

    Chung-Lan Kao

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  1. Kai-Hsi Lu
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  11. Yann-Jang Chen
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Corresponding author

Correspondence to Yann-Jang Chen.

Additional information

Kai-Hsi Lu, Yi-Wei Chen, Ping-Hsing Tsai, and Ming-Long Tsai contributed equally to this work.

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Lu, KH., Chen, YW., Tsai, PH. et al. Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells. Childs Nerv Syst 25, 543–550 (2009). https://doi.org/10.1007/s00381-009-0826-6

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  • DOI: https://doi.org/10.1007/s00381-009-0826-6

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