Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction

被引:63
作者
Eramo, A
Pallini, R
Lotti, F
Sette, G
Patti, M
Bartucci, M
Ricci-Vitiani, L
Signore, M
Stassi, G
Larocca, LM
Crinò, L
Peschle, C
De Maria, R
机构
[1] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy
[2] Catholic Univ, Dept Neurosurg, Rome, Italy
[3] Catholic Univ, Sch Med, Inst Human Pathol, Rome, Italy
[4] Mediterranean Inst Oncol, Catania, Italy
[5] Univ Palermo, Dept Surg & Oncol Sci, I-90133 Palermo, Italy
关键词
D O I
10.1158/0008-5472.CAN-05-1724
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Life expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/ PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenotis caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma, cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma, multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma, resistance to therapeutic treatments.
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收藏
页码:11469 / 11477
页数:9
相关论文
共 39 条
[1]   Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death [J].
Boldin, MP ;
Goncharov, TM ;
Goltsev, YV ;
Wallach, D .
CELL, 1996, 85 (06) :803-815
[2]   A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme [J].
Brandes, AA ;
Turazzi, S ;
Basso, U ;
Pasetto, LM ;
Guglielmi, B ;
Volpin, L ;
Iuzzolino, P ;
Amista, P ;
Pinna, G ;
Scienza, R ;
Ermani, M .
NEUROLOGY, 2002, 58 (12) :1759-1764
[3]   PED/PEA-15:: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis [J].
Condorelli, G ;
Vigliotta, G ;
Cafieri, A ;
Trencia, A ;
Andalò, P ;
Oriente, F ;
Miele, C ;
Caruso, M ;
Formisano, P ;
Beguinot, F .
ONCOGENE, 1999, 18 (31) :4409-4415
[4]   IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins [J].
Conticello, C ;
Pedini, F ;
Zeuner, A ;
Patti, M ;
Zerilli, M ;
Stassi, G ;
Messina, A ;
Peschle, C ;
De Maria, R .
JOURNAL OF IMMUNOLOGY, 2004, 172 (09) :5467-5477
[5]  
De Stasio C, 2001, CANCER RES, V61, P4272
[6]   Medical progress: Brain tumors [J].
DeAngelis, LM .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (02) :114-123
[7]   Control of E2F activity by p21Waf1/Cip1 [J].
Delavaine, L ;
La Thangue, NB .
ONCOGENE, 1999, 18 (39) :5381-5392
[8]  
Eggert A, 2001, CANCER RES, V61, P1314
[9]   Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo [J].
Fulda, S ;
Wick, W ;
Weller, M ;
Debatin, KM .
NATURE MEDICINE, 2002, 8 (08) :808-815
[10]   Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer [J].
Fulda, S ;
Küfer, MU ;
Meyer, E ;
van Valen, F ;
Dockhorn-Dworniczak, B ;
Debatin, KM .
ONCOGENE, 2001, 20 (41) :5865-5877