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.