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TLN-4601 peripheral benzodiazepine receptor (PBR/TSPO) binding properties do not mediate apoptosis but confer tumor-specific accumulation.

Abstract
TLN-4601 is a farnesylated dibenzodiazepinone isolated from Micromonospora sp. with an antiproliferative effect on several human cancer cell lines. Although the mechanism of action of TLN-4601 is unknown, our earlier work indicated that TLN-4601 binds the PBR (peripheral benzodiazepine receptor; more recently known as the translocator protein or TSPO), an 18 kDa protein associated with the mitochondrial permeability transition (mPT) pore. While the exact function of the PBR remains a matter of debate, it has been implicated in heme and steroid synthesis, cellular growth and differentiation, oxygen consumption and apoptosis. Using the Jurkat immortalized T-lymphocyte cell line, documented to have negligible PBR expression, and Jurkat cells stably transfected with a human PBR cDNA, the present study demonstrates that TLN-4601 induces apoptosis independently of PBR expression. As PBRs are overexpressed in brain tumors compared to normal brain, we examined if TLN-4601 would preferentially accumulate in tumors using an intra-cerebral tumor model. Our results demonstrate the ability of TLN-4601 to effectively bind the PBR in vivo as determined by competitive binding assay and receptor occupancy. Analysis of TLN-4601 tissue and plasma indicated that TLN-4601 preferentially accumulates in the tumor. Indeed, drug levels were 200-fold higher in the tumor compared to the normal brain. TLN-4601 accumulation in the tumor (176 μg/g) was also significant compared to liver (24.8 μg/g; 7-fold) and plasma (16.2 μg/mL; 11-fold). Taken together our data indicate that while PBR binding does not mediate cell growth inhibition and apoptosis, PBR binding may allow for the specific accumulation of TLN-4601 in PBR positive tumors.
AuthorsT Bertomeu, V Zvereff, A Ibrahim, S P Zehntner, A Aliaga, P Rosa-Neto, B J Bedell, P Falardeau, H Gourdeau
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 80 Issue 10 Pg. 1572-9 (Nov 15 2010) ISSN: 1873-2968 [Electronic] England
PMID20655882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Dibenzazepines
  • Ligands
  • Receptors, GABA
  • TSPO protein, human
  • diazepinomicin
Topics
  • Animals
  • Antineoplastic Agents (blood, pharmacokinetics, pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Binding, Competitive
  • Blotting, Western
  • Brain (drug effects, metabolism, pathology)
  • Brain Neoplasms (drug therapy, metabolism, pathology)
  • Cell Survival (drug effects)
  • Dibenzazepines (blood, pharmacokinetics, pharmacology, therapeutic use)
  • Dose-Response Relationship, Drug
  • Glioma (drug therapy, metabolism, pathology)
  • Humans
  • Jurkat Cells
  • Ligands
  • Male
  • Membrane Potential, Mitochondrial (drug effects)
  • Molecular Structure
  • Neoplasm Transplantation
  • Positron-Emission Tomography
  • Protein Binding
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA (genetics, metabolism)
  • Transfection

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