EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins

Henrick Horita, Jacqueline Thorburn, Arthur E. Frankel, Andrew Thorburn

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Current treatments for Glioblastoma multiforme (GBM) involve surgery, radiotherapy, and cytotoxic chemotherapy; however, these treatments are not effective and there is an urgent need for better treatments. We investigated GBM cell killing by a novel drug combination involving DT-EGF, an Epidermal Growth Factor Receptor-targeted bacterial toxin, and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) or antibodies that activate the TRAIL receptors DR4 and DR5. DT-EGF kills GBM cells by a non apoptotic mechanism whereas TRAIL kills by inducing apoptosis. GBM cells treated with DT-EGF and TRAIL were killed in a synergistic fashion in vitro and the combination was more effective than either treatment alone in vivo. Tumor cell death with the combination occurred by caspase activation and apoptosis due to DT-EGF positively regulating TRAIL killing by depleting FLIP, a selective inhibitor of TRAIL receptor-induced apoptosis. These data provide a mechanism-based rationale for combining targeted toxins and TRAIL receptor agonists to treat GBM.

Original languageEnglish (US)
Pages (from-to)175-184
Number of pages10
JournalJournal of Neuro-Oncology
Volume95
Issue number2
DOIs
StatePublished - 2009

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Diphtheria Toxin
Immunotoxins
Apoptosis Regulatory Proteins
Glioblastoma
TNF-Related Apoptosis-Inducing Ligand Receptors
Epidermal Growth Factor
Apoptosis
Bacterial Toxins
Drug Combinations
Therapeutics
Caspases
Epidermal Growth Factor Receptor
Cell Death
Radiotherapy
Tumor Necrosis Factor-alpha
Ligands
Drug Therapy
Antibodies
Neoplasms

Keywords

  • Apoptosis
  • Autophagy
  • Diphtheria toxin
  • TRAIL

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

Cite this

EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins. / Horita, Henrick; Thorburn, Jacqueline; Frankel, Arthur E.; Thorburn, Andrew.

In: Journal of Neuro-Oncology, Vol. 95, No. 2, 2009, p. 175-184.

Research output: Contribution to journalArticle

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