The Translocator
Protein (TSPO), previously known as the peripheral-type
benzodiazepine receptor, is a ubiquitous
drug- and
cholesterol-binding protein that is up regulated in several types of
cancer cells. TSPO
drug ligands (e.g.,
diazepam) induce or inhibit
tumor cell proliferation, depending on the dose and tissue origin. We have previously shown that TSPO is expressed in Ehrlich
tumor cells and that
diazepam increases proliferation of these cells in vitro. Here, we investigated the in vivo effects of
diazepam on Ehrlich
tumor growth and the role of TSPO in mediating this process.
Oral administration of
diazepam to mice (3.0mg/kg/day for 7 days) produced plasma and ascitic fluid
drug concentrations of 83.83 and 54.12 nM, respectively.
Diazepam increased Ehrlich
tumor growth, likely due to its ability to increase
tumor cell proliferation and
Reactive Oxygen Species production. Radioligand binding assays and
nucleotide sequencing revealed that Ehrlich
tumor cell TSPO had the same pharmacological and biochemical properties as TSPO described in other
tumor cells. The estimated K(d) for
PK 11195 in Ehrlich
tumor cells was 0.44 nM and 8.70 nM (low and high binding site, respectively). Structurally diverse TSPO
drug ligands with exclusive affinity for TSPO (i.e., 4-
chlordiazepam, Ro5-4864, and
isoquinoline-carboxamide
PK 11195) also increased Ehrlich
tumor growth. However,
clonazepam, a
GABA(A)-specific
ligand with no affinity for TSPO, failed to do so. Taken together, these data suggest that
diazepam induces in vivo Ehrlich
tumor growth in a TSPO-dependent manner.