Abstract | BACKGROUND: 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.
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Authors | Mehran Makvandi, Estifanos D Tilahun, Brian P Lieberman, Redmond-Craig Anderson, Chenbo Zeng, Kuiying Xu, Catherine Hou, Elizabeth S McDonald, Daniel A Pryma, Robert H Mach |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 467
Issue 4
Pg. 1070-5
(Nov 27 2015)
ISSN: 1090-2104 [Electronic] United States |
PMID | 26453012
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Receptors, sigma
- sigma-2 receptor
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Topics |
- Antineoplastic Agents
(administration & dosage, therapeutic use)
- Cell Line, Tumor
- Drug Delivery Systems
- Female
- Humans
- Receptors, sigma
(drug effects)
- Triple Negative Breast Neoplasms
(drug therapy, metabolism)
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