Makvandi Mehran, Tilahun Estifanos D, Lieberman Brian P, Anderson Redmond-Craig, Zeng Chenbo, Xu Kuiying, Hou Catherine, McDonald Elizabeth S, Pryma Daniel A, Mach Robert H
University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
Biochem Biophys Res Commun. 2015 Nov 27;467(4):1070-5. doi: 10.1016/j.bbrc.2015.09.157. Epub 2015 Oct 9.
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.
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.
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.
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.
与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）的复发率高且死亡率增加。与受体阳性乳腺癌不同，TNBC尚无获批的靶向治疗方法。确定TNBC的生物标志物对改善患者护理至关重要。σ-2受体已证实在体内的三阴性乳腺癌中过表达，并已被表征为增殖标志物。本研究的目的是将σ-2受体定义为TNBC治疗性药物递送的靶点和生物标志物。
评估了三种TNBC细胞系：MDA-MB-231、HCC1937和HCC1806。通过竞争性抑制试验测试了σ-2化合物对σ-2受体特异性的药理特性。通过放射性配体受体饱和研究测量σ-2受体表达。将紫杉醇的药物敏感性与与细胞毒性载荷偶联的σ-2靶向化合物SW IV-134进行比较。处理2或48小时后评估细胞活力。评估σ-2阻断以确定SW IV-134的σ-2介导的细胞毒性。在相应的处理时间点测量SW IV-134诱导的半胱天冬酶3/7激活。
SW IV-134是在三个细胞系中的两个中测试的最有效的化合物，并且在所有三个细胞系中效果相似。MDA-MB-231显示出统计学上显著更高的σ-2受体表达，并且也是评估对SW IV-134最敏感的细胞系。
用细胞毒性载荷靶向σ-2受体在所有评估的三个细胞系中均有效，并为未来开发用于治疗TNBC的治疗平台提供了概念验证。
