Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo.
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.
Sakai
M
M
Neuroimmunomodulation Research Group, Department of Pathology, São Paulo University, São Paulo, Brazil.
Ferraz-de-Paula
V
V
Pinheiro
M L
ML
Ribeiro
A
A
Quinteiro-Filho
W M
WM
Rone
M B
MB
Martinez-Arguelles
D B
DB
Dagli
M L Z
ML
Papadopoulos
V
V
Palermo-Neto
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D007546:Isoquinolines / Q000378:metabolism; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism*; D017422:Sequence Analysis, DNA
C463819:Bzrp protein, mouse; D007546:Isoquinolines; D018079:Receptors, GABA; D003975:Diazepam; C037850:PK 11195