The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer.

Autor: Makvandi M; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Tilahun ED; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Lieberman BP; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Anderson RC; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Zeng C; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Xu K; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Hou C; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., McDonald ES; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Pryma DA; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA., Mach RH; University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA. Electronic address: rmach@mail.med.upenn.edu.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2015 Nov 27; Vol. 467 (4), pp. 1070-5. Date of Electronic Publication: 2015 Oct 09.
DOI: 10.1016/j.bbrc.2015.09.157
Abstrakt: Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC.
Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points.
Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134.
Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: