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BCL-2 Family Proteins Modulate Radiosensitivity in Human Malignant Glioma Cells

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Abstract

Radiotherapy is the standard treatment for glioblastoma. Here, we assessed the radiosensitivity of 12 human malignant glioma cell lines in vitro and correlated these data with irradiation-induced cell cycle changes, chemosensitivity profiles and BCL-2 family protein expression. Irradiation at 3 Gy failed to cause major cell cycle perturbations. Radioresistance was associated with collateral sensitivity to the topoisomerase II inhibitors, teniposide and doxorubicin. High levels of BCL-XL and low levels of BAX were independently linked to radioresistance. Ectopic expression of a BAX transgene induced radiosensitization in the LN-18 cell line. Thus, BCL-2 family protein expression modulates radiosensitivity in human glioma cells and targeted alterations in BCL-2 family protein expression are a promising strategy to improve the therapeutic efficacy of radiotherapy for gliomas.

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References

  1. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71: 2585-2597, 1993

    Google Scholar 

  2. Bartussek C, Naumann U, Weller M: Accumulation of mutant p53(V143A) modulates the growth, clonogenicity, and radiochemosensitivity of malignant glioma cells independent of endogenous p53 status. Exp Cell Res 253: 432-439, 1999

    Google Scholar 

  3. Zhivotovsky B, Joseph B, Orrenius S: Tumor radiosensitivity and apoptosis. Exp Cell Res 248: 10-17, 1990

    Google Scholar 

  4. Weller M, Malipiero U, Aguzzi A, Reed JC, Fontana A: Protooncogene BCL-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest 95: 2633-2643, 1995

    Google Scholar 

  5. Weller M, Rieger J, Grimmel C, Van Meir EG, DeTribolet N, Krajewski S, Reed JC, Von Deimling A, Dichgans J: Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses. Int J Cancer 79: 640-644, 1998

    Google Scholar 

  6. Naumann U, Weller M: Retroviral BAX gene transfer fails to sensitize malignant glioma cells to CD95L-induced apoptosis and cancer chemotherapy. Int J Cancer 77: 645-648, 1998

    Google Scholar 

  7. Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M: APO2 ligand: A novel lethal weapon against malignant glioma? FEBS Lett 427: 124-128, 1998

    Google Scholar 

  8. Rosen EM, Fan S, Rockwell S, Goldberg ID: The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic irradiation. Cancer Invest 17: 56-72, 1999

    Google Scholar 

  9. Streffer JR, Schuster M, Pohl U, Belka C, Dichgans J, Bamberg M, Weller M: Irradiation induced clonogenic cell death of human malignant glioma cells does not require CD95/CD95L interactions. Anticancer Res 19: 5265-5269, 1999

    Google Scholar 

  10. Wick W, Furnari FB, Naumann U, Cavenee WK, Weller M: PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene 18: 3936-3943, 1999

    Google Scholar 

  11. Rieger L, Weller M, Bornemann A, Schabet M, Dichgans J, Meyermann R: BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study. J Neurol Sci 155: 68-75, 1998

    Google Scholar 

  12. Newcomb EW, Cohen H, Lee SR, Bhalla SK, Bloom J, Hayes RL, Miller DC: Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2 or BCL-2 genes. Brain Pathol 8: 655-667, 1998

    Google Scholar 

  13. Strik H, Deininger M, Streffer J, Grote E, Wickboldt J, Dichgans J, Weller M, Meyermann R: BCL-2 family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy. J Neurol Neurosurg Psychiatry 67: 763-768, 1999

    Google Scholar 

  14. Sakakura C, Sweeney EA, Shirahama T, Igarashi Y, Hakomori S, Nakatani H, Tsujimoto H, Imanishi T, Ohgaki M, Ohyama T, Yamazaki J, Hagiwara A, Yamaguchi T, Sawai K, Takahashi T: Overexpression of bax sensitizes human breast cancer MCF-7 cells to radiationinduced apoptosis. Int J Cancer 67: 101-105, 1996

    Google Scholar 

  15. Vogelbaum MA, Tong JX, Perugu R, Gutmann DH, Rich KM: Overexpression of bax in human glioma cell lines. J Neurosurg 91: 483-489, 1999

    Google Scholar 

  16. Shu HK, Kim MM, Chen P, Furman F, Julin CM, Israel MA: The intrinsic radioresistance of glioblastomaderived cell lines is associated with a failure of p53 to induce p21 (BAX) expression. Proc Natl Acad Sci USA 95: 14453-14458, 1998

    Google Scholar 

  17. Shinoura N, Yoshida Y, Asai A, Kirino T, Hamada H: Relative level of expression of Bax and Bcl-XL determines the cellular fate of apoptosis/necrosis induced by the overexpression of Bax. Oncogene 18: 5703-5713, 1999

    Google Scholar 

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Streffer, J.R., Rimner, A., Rieger, J. et al. BCL-2 Family Proteins Modulate Radiosensitivity in Human Malignant Glioma Cells. J Neurooncol 56, 43–49 (2002). https://doi.org/10.1023/A:1014448721327

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  • DOI: https://doi.org/10.1023/A:1014448721327

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