Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis

Tobias Longin Haas, Ronald Koschny, Heidrun Holland, Jaromir Sykora, Martin R. Sprick, Tom M. Ganten, Wolfgang Krupp, Manfred Bauer, Peter Ahnert, Jürgen Meixensberger, Henning Walczak

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103 Citazioni (Scopus)

Abstract

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 bortezomib enhanced TRAIL DISC formation upon TRAIL triggering, down-regulation of cFLIPL and activation of the intrinsic apoptosis pathway seemto 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. © 2007 American Association for Cancer Research.
Lingua originaleEnglish
pagine (da-a)3403-3412
Numero di pagine10
RivistaClinical Cancer Research
Volume13
DOI
Stato di pubblicazionePubblicato - 2007

Keywords

  • Cancer Research
  • Oncology

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