Summary
Glioblastomas are among the most difficult neoplasms to treat with continued poor prognosis for long-term survival. Glioblastomas have developed effective mechanisms to resist chemotherapy including levels anti-apoptotic proteins, Bcl-xL and Bcl-2. Chemotherapy agents that promote down-regulation of Bcl-xL and Bcl-2 may enhance sensitivity to chemotherapy in glioblastomas. The ability of the synthetic retinoid N-(4-hydroxyphenyl) retinamide to modulate these anti-apoptotic proteins and to enhance apoptosis and chemotherapy was examined in glioblastoma cells. Expression of Bcl-2 family member proteins Bcl-xL and Bcl-2 were assessed in glioblastomas from three cell lines including U87, U251, and U138. Cells were treated with either retinamide alone or in combination with the chemotherapy agent, BCNU. The incidence of apoptosis was determined with flow cytometry analysis (FACS). Based on Western blots the levels of Bcl-2 and Bcl-xL were decreased in glioblastoma cells after treatment with retinamide. Retinamide treatment resulted in increased ratios of deamidated verses transamidated levels of Bcl-xL in U87 cells. BCNU chemotherapy combined with retinamide markedly down-regulated levels of both Bcl-xL and Bcl-2 proteins in glioblastoma and enhanced the incidence of apoptosis in U87 cells. These studies demonstrate that modulation of levels of the anti-apoptotic proteins, Bcl-xL and Bcl-2, may enhance the sensitivity of glioblastoma toward chemotherapy.
Similar content being viewed by others
References
Y Tsujimoto J Cossman E Jaffe C Croce (1985) ArticleTitleInvolvement of the Bcl-2 gene in human follicular lymphoma Science 228 1440–1443 Occurrence Handle3874430
JC Reed ( 1995) ArticleTitleBcl-2: prevention of apoptosis as a mechanism of drug resistance Hematol Oncol Clin N Am 9 451–473
D Bufalo ParticleDel D Trisciuoglio A Biroccio L Marcocci S Buglioni A Candiloro M Scarsella C Leonetti G Zupi (2001) ArticleTitleBcl-2 overexpression decreases BCNU sensitivity of a human glioblastoma line through enhancement of catalase activity J Cell Biochem 83 473–483 Occurrence Handle10.1002/jcb.1245 Occurrence Handle11596115
D Schiffer P Cavalla A Migheli MT Giordana L Chiado-Piat (1996) ArticleTitleBcl-2 distribution in neuroepithelial tumors: an immunohistochemical study J Neuro-oncol 27 101–109 Occurrence Handle10.1007/BF00177472
Y Takekawa T Sawada I Sakurai (1999) ArticleTitleExpression of apoptosis and its related protein in astrocytic tumors Brain Tumor Pathol 16 11–16 Occurrence Handle10532418
A Korshunov A Golanov R Sycheva I Pronin (1999) ArticleTitlePrognostic value of tumour associated antigen immunoreactivity and apoptosis in cerebral glioblastomas: an analysis of 168 cases J Clin Pathol 52 574–580 Occurrence Handle10645226
C Rodriguez-Pereira JM Suarez-Penaranda F Barros MJ Sobrido M Vazquez-Salvado J Forteza (2001) ArticleTitleAnalysis of 2 antiapoptotic factors in gliomas: Bcl-2 overexpression and p53 mutations Arch Pathol Lab Med 125 218–223 Occurrence Handle11175638
SA Amundson TG Myers D Scudiero S Kitada JC Reed AJ Fornace SuffixJr (2000) ArticleTitleAn informatics approach identifying markers of chemosensitivity in human cancer cell lines Can Res 60 6101–6110
M Nagane A Levitzki A Gazit WK Cavenee HJ Huang (1998) ArticleTitleDrug resistance of human glioblastoma cells conferred by a tumor-specific epidermoid growth factor, through modulation of Bcl-xL and caspase−3-like proteases Proc Natl Acad Sci USA 95 5724–5729 Occurrence Handle10.1073/pnas.95.10.5724 Occurrence Handle9576951
K Mishima TG Johns RB Luwor AM Scott E Stockert AA Jungbluth XD Ji P Suvarna JR Voland LJ Old HJ Huang WK Cavenee (2001) ArticleTitleGrowth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor Can Res 61 5349–5354
Z Jiang X Zheng KM Rich (2003) ArticleTitleDown-regulation of Bcl-2 and Bcl-xL expression with bispecific antisense treatment of glioblastoma cell lines induce cell death J Neurochem 84 273–281 Occurrence Handle10.1046/j.1471-4159.2003.01522.x Occurrence Handle12558990
LA Hansen CC Sigman F Andreola SA Ross GJ Kelloff LM Deluca (2000) ArticleTitleRetinoids in chemoprevention and differentiation therapy Carcinogenesis 21 1271–1279 Occurrence Handle10.1093/carcin/21.7.1271 Occurrence Handle10874003
RM Niles (2000) ArticleTitleRecent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer Nutrition 16 1084–1090 Occurrence Handle10.1016/S0899-9007(00)00436-6 Occurrence Handle11118831
Hong WK, Itri LM: Retinoids and human cancer. In Sporn MB, Roberts AB, Goodman DS, (eds) The Retinoids: Biology, Chemistry, and Medicine. Raven Press, New York, pp 579–630
R Wareel S Frankel W Miller D Scheiberg L Itri W Hittleman R Vyas M Andreef A Tafuri A Jakuboski J Gabrilove M Gordon E Dmitrovsky (1991) ArticleTitleDifferentiation therapy of acute promeylocytic leukemia with tretinoin (all trans retionoic acid) N Eng J Med 324 1385–1393
ZX Chen YQ Xue R Zang RF Tao XM Xia C Li W Wang WY Zu XZ Yao BJ Ling (1991) ArticleTitleA clinical and experimental study on all-trans-retinoic acid-treated acute promyelocytic patients Blood 78 1413–1419 Occurrence Handle1884013
D Delia A Aiello L Lombardi PG Pelicci F Grignani F Formelli S Menard A Costa U Veronesi MA Aerotti (1993) ArticleTitleN-(4-hydroxyphenol) retinamide induces apoptosis of malignant cell lines, including those unresponsive to retinoic acid Can Res 53 6036–6041
M Ponzoni P Bocca V Chiesa A Decensi V Postoia L Rafaphello C Rozzo P Montaldo (1995) ArticleTitleDifferential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation Can Res 55 853–61
C Marth G Bock G Daxenbichler (1985) ArticleTitleEffect of 4-hydroxyphenylretinamide and retinoic acid on proliferation and cell cycle of cultured human breast cancer cells J Natl Cancer Inst 75 871–875 Occurrence Handle2932587
R Supino M Crosti M Clerici A Warlters L Cleris F Zunino F Formelli (1996) ArticleTitleInduction of apoptosis by fenretinide (4-HPR) in human ovarian carcinoma cells and its association with retinoic acid receptor expression Int J Cancer 65 491–97 Occurrence Handle10.1002/(SICI)1097-0215(19960208)65:4<491::AID-IJC17>3.0.CO;2-D Occurrence Handle8621233
N Oridate D Lotan M Mitchell W Hong R Lotan (1995) ArticleTitleInhibition of proliferation and induction of apoptosis in cervical carcinoma cells by retinoids: implications and chemoprevention J Cell Biochem Suppl 23 80–86 Occurrence Handle8747381
R Scher W Saito R Dodge W Richtsmeier R Fine (1998) ArticleTitleFenretinide-induced apoptosis of human head and neck squamous carcinoma cell lines Otolaryngol Head Neck Surg 118 464–471 Occurrence Handle9560096
U Veronesi G Palo ParticleDe E Marubini A Costa F Formelli L Mariani A Decensi T Camerini M Rosselli Turco ParticleDel M Di Mauro R Miceli M Sporn (1999) ArticleTitleRandomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer J␣Natl Cancer Inst 91 1847–56 Occurrence Handle10.1093/jnci/91.21.1847 Occurrence Handle10547391
A Costa G Palo ParticleDe A Decensi F Fomelli F Chiesa M Nava T Camerini E Marubini U Veronesi (1995) ArticleTitleRetinoids in cancer chemoprevention. Clinical trials with the synthetic analogue fenretinide Ann NY J Acad Sci 768 148–162
U Zangemeister-Wittke SH Leech RA Olie AP Simoes-Wust O Gautschi GH Luedke F Natt R Haner P Martin J Hall CM Nalin RA Stahel (2000) ArticleTitleA novel bispecific antisense oligonucleotide inhibiting both Bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells Clin Can Res 6 2547–2555
M Strasberg Rieber U Zangemeister-Wittke M Rieber (2001) ArticleTitlep53-Independent induction of apoptosis in human melanoma cells by a Bcl-2/bcl-xL bispecific antisense oligonucleotide Clin Can Res 7 1446–1451
H Kojima K Endo H Moriyama Y Tanaka ES Alnemri CA Slapak B Teicher D Kufe R Datta (1998) ArticleTitleAbrogation of mitochondrial cytochrome c release and caspase−3 activation in acquired multidrug resistance J Biol Chem 273 16647–16650 Occurrence Handle10.1074/jbc.273.27.16647 Occurrence Handle9642215
BE Deverman BL Cook SR Manson RA Niederhoff EM Langer I Rosova LA Kulans X Fu JS Weinberg JW Heinecke KA Roth SJ Weintraub (2002) ArticleTitleBcl-xL deamidation is a critical switch in the regulation of the response to DNA damage Cell 111 51–62 Occurrence Handle10.1016/S0092-8674(02)00972-8 Occurrence Handle12372300
T Takehara H Takahashi (2003) ArticleTitleSuppression of Bcl-xL deamidation in human hepatocellular carcinomas Can Res 63 3054–3057
SE Kaba AP Kyritsis C Conrad MJ Gleason R Newman VA Levin WK Yung (1997) ArticleTitleThe treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin) J Neurooncol 34 145–151 Occurrence Handle10.1023/A:1005743707803 Occurrence Handle9210061
S Phuphanich C Scott AJ Fischbach C Langer WK Yung (1997) ArticleTitleAll-trans-retinoic acid: a phase II Radiation Therapy Oncology Group study (RTOG 91-13) in patients with recurrent malignant astrocytoma J Neurooncol 34 193–200 Occurrence Handle10.1023/A:1005765915288 Occurrence Handle9210068
KA Jaeckle KR Hess WK Yung H Greenberg H Fine D Schiff IF Pollack J Kuhn K Fink M Mehta T Cloughesy MK Nicholas S Chang M Prados (2003) ArticleTitleNorth American Brain Tumor Consortium.Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study J Clin Oncol 21 2305–2311 Occurrence Handle10.1200/JCO.2003.12.097 Occurrence Handle12805331
V Puduvalli Y Saito R Xu G Kouraklis V Levin A Kyritsis (1999) ArticleTitleFenretinide activates caspases and induces apoptosis in gliomas Clin Can Res 5 2230–2235
VK Puduvalli WKA Yung M Prados J Kuhn K Hess M Groves V Levin S Chang J Zwiebel T Cloughesy ( 2003) ArticleTitleNorth American Brain Tumor Consortium. Phase II trial of fenretinide in patients with recurrent malignant gliomas - A North American Brain Tumor Consortium study Proc Am Soc Clin Oncol 22 105
P Boya MC Morales RA Gonzalez-Polo K Andreau I Gourdier JL Perfettini N Larochette A Deniaud F Baran-Marszak R Fagard J Feuillard A Asumendi M Raphael B Pau C Brenner G Kroemer (2003) ArticleTitleThe chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family Oncogene 22 6220–6230 Occurrence Handle10.1038/sj.onc.1206827 Occurrence Handle13679861
JC Shen TT Wang S Chang SD Hursting (1999) ArticleTitleMechanistic studies of the effects of the retinoid N-(4-hydroxyphenyl)retinamide on prostate cancer cell growth and apoptosis Mol Car 24 160–168 Occurrence Handle10.1002/(SICI)1098-2744(199903)24:3<160::AID-MC2>3.0.CO;2-M
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lytle, R.A., Jiang, Z., Zheng, X. et al. Retinamide-Induced Apoptosis in Glioblastomas is Associated with Down-Regulation of Bcl-xL and Bcl-2 Proteins. J Neurooncol 74, 225–232 (2005). https://doi.org/10.1007/s11060-005-7305-z
Issue Date:
DOI: https://doi.org/10.1007/s11060-005-7305-z