This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koschny, R. Articles by Walczak, H. Search for Related Content PubMed PubMed Citation Articles by Koschny, R. Articles by Walczak, H.

Bortezomib Sensitizes Primary Human Astrocytoma Cells of WHO Grades I to IV for Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis

Author's Affiliations: ¹ Division of Apoptosis Regulation (D040), German Cancer Research Center (DKFZ); ² Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany; ³ Biotechnical-Biomedical Centre (BBZ), Faculty of Medicine, ⁴ Clinic of Neurosurgery, ⁵ Institute of Neuropathology, and ⁶ Institute for Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany; and ⁷ Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, Amsterdam, the Netherlands

Requests for reprints: Henning Walczak, Division for Apoptosis Regulation, D040, Germany Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg D-69120, Germany. Phone: 49-6221-423700; Fax: 49-6221-423699; E-mail: h.walczak{at}dkfz.de.

Purpose: 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.

Experimental Design: 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 bortezomibenhanced 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.

Conclusion: 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.

This article has been cited by other articles:

				D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]

				R. Koschny, J. Sykora, H. Walczak, T. M. Ganten, T. L. Haas, M. R. Sprick, H. Holland, P. Ahnert, W. Krupp, J. Meixensberger, et al. Bortezomib-Mediated Up-Regulation of TRAIL-R1 and TRAIL-R2 Is Not Necessary for but Contributes to Sensitization of Primary Human Glioma Cells to TRAIL Clin. Cancer Res., November 1, 2007; 13(21): 6541 - 6542. [Full Text] [PDF]

				A. P. Kyritsis, F. Tachmazoglou, J. S. Rao, and V. K. Puduvalli Bortezomib Sensitizes Human Astrocytoma Cells to Tumor Necrosis Factor Related Apoptosis-Inducing Ligand Induced Apoptosis Clin. Cancer Res., November 1, 2007; 13(21): 6540 - 6540. [Full Text] [PDF]

				M. J.S. Dyer, M. MacFarlane, and G. M. Cohen Barriers to Effective TRAIL-Targeted Therapy of Malignancy J. Clin. Oncol., October 1, 2007; 25(28): 4505 - 4506. [Full Text] [PDF]