In vitro effects of topotecan and ionizing radiation on TRAIL/Apo2L-mediated apoptosis in malignant glioma.
The survival of patients with malignant gliomas is still unsatisfactory despite multimodality treatment, therefore new therapeutic strategies are required. Tumor necrosis factor apoptosis related ligand (TRAIL/Apo2L), a member of the tumor necrosis factor superfamily, may induce apoptotic cell death in several tumors, but not in normal cells, upon binding with specific receptors. In the present study, the expression and function of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) has been investigated in five human glioma cell lines (U87, U138, U373, A172, SW1783) in ex vivo tumors and in primary cultures obtained from the tumors. Our data show that gliomas preferentially express TRAIL R2 and that treatment with topotecan, a topoisomerase I inhibitor, significantly up-regulates its expression as detected by flow cytometry and western blotting. Moreover, in most cases, treatment with topotecan resulted in an increased sensitivity to TRAIL-dependent apoptosis, although cyclohexymide had to be added to induce apoptosis. On glioma cell lines, the effects of irradiation on TRAIL receptors were also analysed. In our experimental conditions, irradiation with 2 Gy had a modest additive effect on TRAIL-dependent apoptosis and was not able to modulate TRAIL receptor expression.
Ciusani
Emilio
E
Department of Clinical Investigation, National Neurological Institute C. Besta, Via Celoria, Milan, Italy. eciusani@istituto-besta.it
Croci
Danilo
D
Gelati
Maurizio
M
Calatozzolo
Chiara
C
Sciacca
Francesca
F
Fumagalli
Luisa
L
Balzarotti
Marco
M
Fariselli
Laura
L
Boiardi
Amerigo
A
Salmaggi
Andrea
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005910:Glioma / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009423:Nervous System Neoplasms / Q000378:metabolism* / Q000628:therapy; D011839:Radiation, Ionizing; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D019772:Topotecan / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019772:Topotecan
Nat Med. 2001 Apr;7(4):383-5
11283636
J Urol. 2001 Jan;165(1):263-70
11125422
J Neurooncol. 2002 Mar;57(1):27-36
12125964
Pharm World Sci. 1997 Jun;19(3):119-25
9259027
Nat Genet. 1997 Oct;17(2):141-3
9326928
Neuro Oncol. 2003 Jan;5(1):8-13
12626128
Cell. 1997 Feb 7;88(3):355-65
9039262
Oncology (Williston Park). 1998 Feb;12(2):233-40; discussion 240, 246
9507524
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1754-9
10677530
Br J Cancer. 2003 Jan 27;88(2):298-306
12610517
Blood. 2001 May 1;97(9):2596-603
11313247
Hepatology. 2000 Sep;32(3):482-90
10960439
Biochem Pharmacol. 2002 Mar 1;63(5):881-7
11911840
Oncogene. 2001 Sep 13;20(41):5789-98
11593384
FEBS Lett. 2001 Sep 7;505(1):179-84
11557065
Nat Rev Cancer. 2002 Jun;2(6):420-30
12189384
Cancer Res. 2001 Feb 1;61(3):1162-70
11221847
Anticancer Res. 1997 Nov-Dec;17 (6B):4127-34
9428346
J Clin Invest. 1999 Jul;104(2):155-62
10411544
Immunol Today. 1992 May;13(5):151-3
1322675
Oncogene. 2001 Jul 12;20(31):4128-37
11464279
Scand J Immunol. 1995 May;41(5):504-8
7725070
Nat Med. 1999 Feb;5(2):157-63
9930862
Cancer Res. 1998 Apr 15;58(8):1593-8
9563466
Cancer Res. 2000 Feb 15;60(4):847-53
10706092
Oncogene. 2001 Apr 19;20(17):2190-6
11360204
Eur J Pharmacol. 2001 Jan 19;412(1):21-5
11166732
Cancer Res. 2000 Oct 15;60(20):5754-60
11059770