The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer.
The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer.
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DOI：
10.1016/j.bbrc.2015.09.157
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发表时间：
2015-11-27
影响因子：
3.1
通讯作者：
Mach RH
中科院分区：
文献类型：
--
作者：
Makvandi M;Tilahun ED;Lieberman BP;Anderson RC;Zeng C;Xu K;Hou C;McDonald ES;Pryma DA;Mach RH
与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）具有高复发率和更高的死亡率。与受体阳性乳腺癌相比，目前尚无批准的针对三阴乳腺癌的靶向治疗方法。确定TNBC的生物标志物对提高患者护理水平具有重要意义。sigma-2受体已被证明在体内三阴性乳腺癌中过度表达，并被定性为增殖的标志。本研究的目的是确定sigma-2受体作为TNBC治疗药物递送的靶标和生物标志物。三种TNBC细胞系分别为MDA-MB-231、HCC1937和HCC1806。通过竞争性抑制实验测试Sigma-2化合物对Sigma-2受体的药理学特性。通过放射性配体受体饱和度研究测量Sigma-2受体的表达。紫杉醇的药物敏感性与sigma-2靶向化合物偶联到细胞毒性载荷SW IV-134进行了比较。处理2小时或48小时后评估细胞活力。评估Sigma-2阻断以确定Sigma-2介导的SW IV-134细胞毒性。在相应的处理时间点检测SW IV-134诱导的Caspase 3/7激活情况。是在三种细胞系中的两种中测试的最有效的化合物，并且在所有三种细胞系中都同样有效。MDA-MB-231显示出具有统计学意义的更高的sigma-2受体表达，也是对SW IV-134最敏感的细胞系。利用细胞毒性载荷靶向sigma-2受体在所有评估的三种细胞系中都是有效的，并为未来开发治疗TNBC的治疗平台提供了概念证明。
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 hours. 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. 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.