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SR31747A is a sigma receptor ligand exhibiting antitumoural activity both in vitro and in vivo.

Berthois Y, Bourrié B, Galiègue S, Vidal H, Carayon P, Martin PM, Casellas P - Br. J. Cancer (2003)

Bottom Line: In an attempt to decipher the SR31747A mode of action, we found that the two binding sites may not fully account for this activity.Indeed, while competitive experiments indicated that EBP prevails in mediating SR31747A antiproliferative activity, an analysis of the expression of both receptors indicated that the cellular sensitivity to SR31747A is not correlated with either EBP or SR-BP expression.Preliminary binding studies demonstrated that SR31747A also binds to sigma 2, a protein that has not yet been cloned, but which is considered as a potential marker of the proliferative status of tumour cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de cancérologie expérimentale EA2671, IFR Jean Roche, Faculté de Médecine Secteur Nord, Marseille, France.

ABSTRACT
SR31747A is a recently described sigma receptor ligand that binds SR31747A-binding protein 1 (SR-BP) and emopamil-binding protein (EBP) (also called the sigma 1 receptor and the human sterol isomerase (HSI), respectively), and has immunoregulatory and antiproliferative activities. To further investigate its antitumour activity and focusing on cancers, which are sensitive to the molecule, we measured the proliferation of different human epithelial breast or prostate cancer cell lines following in vitro and in vivo SR31747A treatment. Firstly, in vitro, we found that nanomolar concentrations of SR31747A dramatically inhibited cell proliferation in both hormono-responsive and -unresponsive cancer cell lines. Secondly, tumour development was significantly decreased in mice treated with SR31747A. In an attempt to decipher the SR31747A mode of action, we found that the two binding sites may not fully account for this activity. Indeed, while competitive experiments indicated that EBP prevails in mediating SR31747A antiproliferative activity, an analysis of the expression of both receptors indicated that the cellular sensitivity to SR31747A is not correlated with either EBP or SR-BP expression. These data suggest that additional binding sites may exist. Preliminary binding studies demonstrated that SR31747A also binds to sigma 2, a protein that has not yet been cloned, but which is considered as a potential marker of the proliferative status of tumour cells. Altogether, our data demonstrate the antitumoural activity of SR31747A both in vitro and in vivo in two different cancer models, broaden the spectrum of its binding proteins and enhance the potential for further therapeutic development of the molecule.

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Effect of pentazocine (A) or cholesterol (B) on the inhibition of mitogenesis in different cell lines induced by SR31747A. (A) Two concentrations of (+) pentazocine were tested: control (○), 10−6 M (•) and 10−5 M (□). (B) Four cholesterol concentrations were tested: control (○), 1 μg ml−1 (•), 2 μg ml−1 (□), 10 μg ml−1 (▪) and 20 μg ml−1 (△). Treatments were performed in low lipid serum concentrations (0.1% FBS for breast cancer cell lines or 1% for prostate cell lines). Representative curves are shown: MCF7, MDA-MB-231 for breast cancer cell lines, and DU145 and PC3 for prostate cancer cell lines. The results are expressed as a percentage of MTT conversion measured in untreated cells.
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fig3: Effect of pentazocine (A) or cholesterol (B) on the inhibition of mitogenesis in different cell lines induced by SR31747A. (A) Two concentrations of (+) pentazocine were tested: control (○), 10−6 M (•) and 10−5 M (□). (B) Four cholesterol concentrations were tested: control (○), 1 μg ml−1 (•), 2 μg ml−1 (□), 10 μg ml−1 (▪) and 20 μg ml−1 (△). Treatments were performed in low lipid serum concentrations (0.1% FBS for breast cancer cell lines or 1% for prostate cell lines). Representative curves are shown: MCF7, MDA-MB-231 for breast cancer cell lines, and DU145 and PC3 for prostate cancer cell lines. The results are expressed as a percentage of MTT conversion measured in untreated cells.

Mentions: We tested whether the inhibition of cell proliferation is mediated by either SR-BP or EBP. Firstly, to discriminate between the two proteins, we used the sigma 1 ligand (+) pentazocine that binds to SR-BP, but does not bind EBP (Jbilo et al, 1997). As shown in Figure 3Figure 3


SR31747A is a sigma receptor ligand exhibiting antitumoural activity both in vitro and in vivo.

Berthois Y, Bourrié B, Galiègue S, Vidal H, Carayon P, Martin PM, Casellas P - Br. J. Cancer (2003)

Effect of pentazocine (A) or cholesterol (B) on the inhibition of mitogenesis in different cell lines induced by SR31747A. (A) Two concentrations of (+) pentazocine were tested: control (○), 10−6 M (•) and 10−5 M (□). (B) Four cholesterol concentrations were tested: control (○), 1 μg ml−1 (•), 2 μg ml−1 (□), 10 μg ml−1 (▪) and 20 μg ml−1 (△). Treatments were performed in low lipid serum concentrations (0.1% FBS for breast cancer cell lines or 1% for prostate cell lines). Representative curves are shown: MCF7, MDA-MB-231 for breast cancer cell lines, and DU145 and PC3 for prostate cancer cell lines. The results are expressed as a percentage of MTT conversion measured in untreated cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747535&req=5

fig3: Effect of pentazocine (A) or cholesterol (B) on the inhibition of mitogenesis in different cell lines induced by SR31747A. (A) Two concentrations of (+) pentazocine were tested: control (○), 10−6 M (•) and 10−5 M (□). (B) Four cholesterol concentrations were tested: control (○), 1 μg ml−1 (•), 2 μg ml−1 (□), 10 μg ml−1 (▪) and 20 μg ml−1 (△). Treatments were performed in low lipid serum concentrations (0.1% FBS for breast cancer cell lines or 1% for prostate cell lines). Representative curves are shown: MCF7, MDA-MB-231 for breast cancer cell lines, and DU145 and PC3 for prostate cancer cell lines. The results are expressed as a percentage of MTT conversion measured in untreated cells.
Mentions: We tested whether the inhibition of cell proliferation is mediated by either SR-BP or EBP. Firstly, to discriminate between the two proteins, we used the sigma 1 ligand (+) pentazocine that binds to SR-BP, but does not bind EBP (Jbilo et al, 1997). As shown in Figure 3Figure 3

Bottom Line: In an attempt to decipher the SR31747A mode of action, we found that the two binding sites may not fully account for this activity.Indeed, while competitive experiments indicated that EBP prevails in mediating SR31747A antiproliferative activity, an analysis of the expression of both receptors indicated that the cellular sensitivity to SR31747A is not correlated with either EBP or SR-BP expression.Preliminary binding studies demonstrated that SR31747A also binds to sigma 2, a protein that has not yet been cloned, but which is considered as a potential marker of the proliferative status of tumour cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de cancérologie expérimentale EA2671, IFR Jean Roche, Faculté de Médecine Secteur Nord, Marseille, France.

ABSTRACT
SR31747A is a recently described sigma receptor ligand that binds SR31747A-binding protein 1 (SR-BP) and emopamil-binding protein (EBP) (also called the sigma 1 receptor and the human sterol isomerase (HSI), respectively), and has immunoregulatory and antiproliferative activities. To further investigate its antitumour activity and focusing on cancers, which are sensitive to the molecule, we measured the proliferation of different human epithelial breast or prostate cancer cell lines following in vitro and in vivo SR31747A treatment. Firstly, in vitro, we found that nanomolar concentrations of SR31747A dramatically inhibited cell proliferation in both hormono-responsive and -unresponsive cancer cell lines. Secondly, tumour development was significantly decreased in mice treated with SR31747A. In an attempt to decipher the SR31747A mode of action, we found that the two binding sites may not fully account for this activity. Indeed, while competitive experiments indicated that EBP prevails in mediating SR31747A antiproliferative activity, an analysis of the expression of both receptors indicated that the cellular sensitivity to SR31747A is not correlated with either EBP or SR-BP expression. These data suggest that additional binding sites may exist. Preliminary binding studies demonstrated that SR31747A also binds to sigma 2, a protein that has not yet been cloned, but which is considered as a potential marker of the proliferative status of tumour cells. Altogether, our data demonstrate the antitumoural activity of SR31747A both in vitro and in vivo in two different cancer models, broaden the spectrum of its binding proteins and enhance the potential for further therapeutic development of the molecule.

Show MeSH
Related in: MedlinePlus