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

Biochem Pharmacol. 2010 Nov 15;80(10):1572-9. doi: 10.1016/j.bcp.2010.07.018. Epub 2010 Jul 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Binding, Competitive
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Survival / drug effects
  • Dibenzazepines / blood
  • Dibenzazepines / pharmacokinetics
  • Dibenzazepines / pharmacology*
  • Dibenzazepines / therapeutic use
  • Dose-Response Relationship, Drug
  • Glioma / drug therapy
  • Glioma / metabolism
  • Glioma / 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
  • Receptors, GABA / metabolism*
  • Transfection


  • Antineoplastic Agents
  • Dibenzazepines
  • Ligands
  • Receptors, GABA
  • TSPO protein, human
  • diazepinomicin