Neuroimmunomodulation Research Group, Department of Pathology, São Paulo University, São Paulo, Brazil.
Eur J Pharmacol. 2010 Jan 25;626(2-3):131-8. doi: 10.1016/j.ejphar.2009.09.036. Epub 2009 Sep 24.
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.
转位蛋白（TSPO）以前称为外周型苯二氮䓬受体，是一种普遍存在的药物和胆固醇结合蛋白，在几种类型的癌细胞中上调。TSPO 药物配体（例如，地西泮）根据剂量和组织来源诱导或抑制肿瘤细胞增殖。我们之前已经表明 TSPO 在 Ehrlich 肿瘤细胞中表达，并且地西泮在体外增加这些细胞的增殖。在这里，我们研究了地西泮对 Ehrlich 肿瘤生长的体内影响以及 TSPO 在介导该过程中的作用。每天给小鼠口服地西泮（3.0mg/kg/天，共 7 天），可产生分别为 83.83 和 54.12nM 的血浆和腹水药物浓度。地西泮增加了 Ehrlich 肿瘤的生长，可能是由于其增加肿瘤细胞增殖和活性氧物质产生的能力。放射性配体结合测定和核苷酸测序表明，Ehrlich 肿瘤细胞的 TSPO 具有与其他肿瘤细胞中描述的 TSPO 相同的药理学和生化特性。PK 11195 在 Ehrlich 肿瘤细胞中的估计 K(d)为 0.44nM 和 8.70nM（低和高结合位点，分别）。具有 TSPO 特异性亲和力的结构多样的 TSPO 药物配体（即 4-氯地西泮、Ro5-4864 和异喹啉-羧酰胺 PK 11195）也增加了 Ehrlich 肿瘤的生长。然而，没有 TSPO 亲和力的 GABA(A)特异性配体氯硝西泮则没有。总之，这些数据表明地西泮以 TSPO 依赖的方式诱导体内 Ehrlich 肿瘤生长。
