Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
OBJECTIVE
Malignant gliomas are the most aggressive human brain tumors without any curative treatment. The antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gliomas has thus far only been thoroughly established in tumor cell lines. In the present study, we investigated the therapeutic potential of TRAIL in primary human glioma cells.


METHODS
We isolated primary tumor cells from 13 astrocytoma and oligoastrocytoma patients of all four WHO grades of malignancy and compared the levels of TRAIL-induced apoptosis induction, long-term tumor cell survival, caspase, and caspase target cleavage.


RESULTS
We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Regardless of the tumor heterogeneity, cotreatment with the proteasome inhibitor bortezomib efficiently sensitized all primary glioma samples for TRAIL-induced apoptosis and tremendously reduced their clonogenic survival. Due to the pleiotropic effect of bortezomib-enhanced TRAIL DISC formation upon TRAIL triggering, down-regulation of cFLIP(L) and activation of the intrinsic apoptosis pathway seem to cooperatively contribute to the antitumor effect of bortezomib/TRAIL cotreatment.


CONCLUSIONS
TRAIL sensitivity of tumor cell lines is not a reliable predictor for the behavior of primary tumor cells. The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by bortezomib cotreatment might, however, provide a powerful therapeutic option for glioma patients.
Koschny
Ronald
R
Division of Apoptosis Regulation (D040), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Holland
Heidrun
H
Sykora
Jaromir
J
Haas
Tobias L
TL
Sprick
Martin R
MR
Ganten
Tom M
TM
Krupp
Wolfgang
W
Bauer
Manfred
M
Ahnert
Peter
P
Meixensberger
Jürgen
J
Walczak
Henning
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D001897:Boronic Acids; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib