title: 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.
authors.affiliation: Thallion Pharmaceuticals Inc., 7150 Alexander-Fleming, Montréal, QC, H4S 2C8, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Bertomeu
authors.forename: V
authors.initials: V
authors.lastname: Zvereff
authors.forename: A
authors.initials: A
authors.lastname: Ibrahim
authors.forename: S P
authors.initials: SP
authors.lastname: Zehntner
authors.forename: A
authors.initials: A
authors.lastname: Aliaga
authors.forename: P
authors.initials: P
authors.lastname: Rosa-Neto
authors.forename: B J
authors.initials: BJ
authors.lastname: Bedell
authors.forename: P
authors.initials: P
authors.lastname: Falardeau
authors.forename: H
authors.initials: H
authors.lastname: Gourdeau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001667:Binding, Competitive; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003984:Dibenzazepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D003984:Dibenzazepines; D008024:Ligands; D018079:Receptors, GABA; C499229:TSPO protein, human; C492422:diazepinomicin