Peripheral-type benzodiazepines inhibit proliferation of astrocytes in culture

Bruce, J.; Ramirez, Arnold M.; Lin, Lin; Oracion, A.; Agarwal, Rekha; Norenberg, Michael D.

doi:10.1016/0006-8993(91)91369-c

Cited by 23 publications

(17 citation statements)

References 12 publications

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“…At nanomolar concentrations, TSPO-specific ligands had no effect on cell growth, confirming the findings of Bruce et al (31). The role of TSPO in PK11195-induced apoptosis is controversial.…”

Section: Discussionsupporting

confidence: 86%

PK11195 enhances chemosensitivity to cisplatin and paclitaxel in human endometrial and ovarian cancer cells

Takai

Ueda²,

Nishida³

et al. 2009

Int J Mol Med

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Abstract. The potential anticancer agent 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a translocator protein ligand, facilitates the induction of cell death by a variety of cytotoxic and chemotherapeutic agents in various human tumor cell lines. The purpose of this study was to elucidate the effect of PK11195 on three endometrial cancer cell lines, two ovarian cancer cell lines and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of PK11195 alone or in combination with chemotherapeutic drugs (cisplatin, paclitaxel), and its effect on cell growth, the cell cycle, apoptosis and related measurements was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that all endometrial and ovarian cancer cell lines were sensitive to the growthinhibitory effect of PK11195, although normal endometrial epithelial cells were viable after treatment with the same doses of PK11195 that induced growth inhibition in endometrial and ovarian cancer cells. Synergistic anti-neoplastic effects were obtained by a combination of PK11195 with cytostatic drugs. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to apoptosis. These results suggest that PK11195 alone or in combination with chemotherapeutic drugs might be a new therapeutic option for the treatment of endometrial and ovarian cancers.

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Section: Discussionsupporting

confidence: 86%

PK11195 enhances chemosensitivity to cisplatin and paclitaxel in human endometrial and ovarian cancer cells

Takai

Ueda²,

Nishida³

et al. 2009

Int J Mol Med

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“…The presence of an amino acid sequence able to inhibit PBR PBR also has been involved in the regulation of cell proliferation, where high-affinity PBR ligands have been shown at micromolar concentrations to inhibit cell proliferation (Wang et al, 1984;Bruce et al, 1991;Hardwick et al, 1999;Maaser et al, 2001), probably via programmed cell death (Hirsch et al, 1998;Maaser et al, 2001). Studies using the TAT-STPH-STP peptide on the MDA-MB-231 aggressive human breast cancer cell line showed that the peptide failed to block the inhibitory effect of micromolar concentrations of Ro5-4864 on cell proliferation (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Peptide Antagonist to the Peripheral-Type Benzodiazepine Receptor That Inhibits Hormone-Stimulated Leydig Cell Steroid Formation

Gazouli

Han²,

Papadopoulos³

2002

J Pharmacol Exp Ther

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Peripheral-type benzodiazepine receptor (PBR) is an 18-kDa high-affinity cholesterol and drug ligand-binding protein involved in various cell functions, including cholesterol transport and steroid biosynthesis. To aid our investigation of the biological function of PBR, we have set out to identify functional antagonists. By screening phage display libraries, we have identified peptides that displace the high-affinity PBR benzodiazepine drug ligand, . Among these peptides, STPHSTP was the most potent (IC 50 ϭ 10 M). All of the isolated peptides showed a conserved motif STXXXXP. The role of these peptides in Leydig cell steroidogenesis was examined using a transducible peptide composed of the TAT domain of human immunodeficiency virus and the peptides under investigation. Synthesized peptides efficiently transduced into MA-10 Leydig cells, and the peptide TAT-STPHSTP inhibited Ro5-4864-and human chorionic gonadotropin-stimulated steroid production in a dose-dependent manner (ED 50 ϭ 5 M). TAT-STPHSTP behaved as a competitive PBR antagonist, which did not affect 22R-hydroxycholesterolsupported steroidogenesis. These results yield leads for the development of potent PBR antagonists and indicate that endogenous PBR agonist-receptor interaction is critical for hormone-induced steroidogenesis.Peripheral-type benzodiazepine receptor (PBR) was originally discovered because it binds the benzodiazepine diazepam with relatively high affinity (Braestrup and Squires, 1977). It was subsequently described as a multimeric complex composed of the 18-kDa receptor protein, the 34-kDa voltage-dependent anion channel protein required for benzodiazepine binding (McEnery et al., 1992;Garnier et al., 1994), and the 30-kDa adenine nucleotide carrier (McEnery et al., 1992) of an as yet unknown function in the complex. Although PBR is present in most tissues examined, it is particularly abundant in steroid-producing tissues where it is found in the outer mitochondrial membrane (Papadopoulos, 1993;Gavish et al., 1999; Casellas et al., 2002). Using high-affinity PBR drug ligands, such as the isoquinoline carboxamide PK 11195 and the benzodiazepine Ro5-4864, it was shown that PBR is involved in the transport of the substrate cholesterol into mitochondria (Papadopoulos, 1993), the ratedetermining and hormone-dependent step in steroid biosynthesis. Further studies using PBR-mutant steroidogenic cells (Papadopoulos et al., 1997) and deletion mutation analysis of the 18-kDa PBR protein (Li and Papadopoulos, 1998) demonstrated the determining role of this protein in cholesterol transport. More recently, PBR was shown to be a high-affinity cholesterol-binding protein (Lacapère et al., 2001;Li et al., 2001b). In addition to its function in steroidogenesis, PBR has been also shown to be implicated in mitochondrial respiration (Hirsch et al., 1989), apoptosis (Hirsch et al., 1998;Papadopoulos et al., 1999), and cell proliferation (Miettinen et al., 1995;Hardwick et al., 1999).In addition to isoquinolines and benzodiazepines (Papadopoulos, 1993...

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“…Our laboratory, as well as others, has previously shown that PBR ligands regulate cell proliferation. [7][8][9][10][11][13][14][15][16][17] The in vivo behavior of the cells, however, differs from their in vitro behavior where no differences in the rates of cell proliferation between the MDA-231 PH and PL is seen. This may be due to a minimum of PBR levels required for cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Increased expression of PBR has been found in numerous tumor types and PBR has been shown to regulate the differentiation state and proliferation rates of several cancer cell lines. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] Over the past several years our laboratory has examined the role of PBR in breast cancer using the MDA-231 cell line. While examining MDA-231 cells from various origins we observed variations in their PBR levels.…”

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confidence: 99%

Peripheral-type benzodiazepine receptor levels correlate with the ability of human breast cancer MDA-MB-231 cell line to grow in scid mice

et al. 2001

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Peripheral-type benzodiazepines inhibit proliferation of astrocytes in culture

Cited by 23 publications

References 12 publications

PK11195 enhances chemosensitivity to cisplatin and paclitaxel in human endometrial and ovarian cancer cells

PK11195 enhances chemosensitivity to cisplatin and paclitaxel in human endometrial and ovarian cancer cells

Identification of a Peptide Antagonist to the Peripheral-Type Benzodiazepine Receptor That Inhibits Hormone-Stimulated Leydig Cell Steroid Formation

Peripheral-type benzodiazepine receptor levels correlate with the ability of human breast cancer MDA-MB-231 cell line to grow in scid mice

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