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

Biochemical Pharmacology
T BertomeuHenriette Gourdeau

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...Continue Reading

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Citations

Jun 28, 2011·Regional Anesthesia and Pain Medicine·Markus F StevensSebastian Braun
Feb 1, 2011·Journal of Bioscience and Bioengineering·Chia-Che ChangYu-Hong Wei
Apr 8, 2014·Genes, Chromosomes & Cancer·Vera RiehmerUNKNOWN German Glioma Network
Jan 20, 2017·Cell Cycle·Guo-Jun LiuRichard B Banati

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