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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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Measurement of EBP and SRBP1 sites in breast or prostatic cancer epithelial cell lines grown in 0.1 or 1% FBS, respectively. (A) EBP and SR-BP numbers were determined by flow cytometric analysis of immunofluorescent-stained cells, as described in Material and Methods. For comparative purposes, EBP and SR-BP sites were also evaluated on normal cells, lymphocytes and monocytes. (B,C): SR31747A IC50 is plotted against SR-BP receptor density (B) or EBP density (C).
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fig4: Measurement of EBP and SRBP1 sites in breast or prostatic cancer epithelial cell lines grown in 0.1 or 1% FBS, respectively. (A) EBP and SR-BP numbers were determined by flow cytometric analysis of immunofluorescent-stained cells, as described in Material and Methods. For comparative purposes, EBP and SR-BP sites were also evaluated on normal cells, lymphocytes and monocytes. (B,C): SR31747A IC50 is plotted against SR-BP receptor density (B) or EBP density (C).

Mentions: In an attempt to correlate the growth-inhibitory activity of SR31747A with the presence of its receptors, we evaluated EBP and SR-BP expression levels by flow cytometry using specific antibodies in the breast and prostatic cancer cell lines used in this study. Our results reported in Figure 4Figure 4


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)

Measurement of EBP and SRBP1 sites in breast or prostatic cancer epithelial cell lines grown in 0.1 or 1% FBS, respectively. (A) EBP and SR-BP numbers were determined by flow cytometric analysis of immunofluorescent-stained cells, as described in Material and Methods. For comparative purposes, EBP and SR-BP sites were also evaluated on normal cells, lymphocytes and monocytes. (B,C): SR31747A IC50 is plotted against SR-BP receptor density (B) or EBP density (C).
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Measurement of EBP and SRBP1 sites in breast or prostatic cancer epithelial cell lines grown in 0.1 or 1% FBS, respectively. (A) EBP and SR-BP numbers were determined by flow cytometric analysis of immunofluorescent-stained cells, as described in Material and Methods. For comparative purposes, EBP and SR-BP sites were also evaluated on normal cells, lymphocytes and monocytes. (B,C): SR31747A IC50 is plotted against SR-BP receptor density (B) or EBP density (C).
Mentions: In an attempt to correlate the growth-inhibitory activity of SR31747A with the presence of its receptors, we evaluated EBP and SR-BP expression levels by flow cytometry using specific antibodies in the breast and prostatic cancer cell lines used in this study. Our results reported in Figure 4Figure 4

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