Division of Radiological Sciences, Department of Radiology, Washington University School of Medicine, St Louis, MO, USA.
Br J Cancer. 2013 Oct 29;109(9):2368-77. doi: 10.1038/bjc.2013.593. Epub 2013 Oct 8.
The sigma-2 receptor has been validated as a biomarker for proliferating tumours. Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria into the cytosol, leading to apoptosis. In this study, we investigated a sigma-2 ligand as a tumour-targeting drug delivery agent for treating ovarian cancer.
A sigma-2 ligand, SW 43, was conjugated with a Smac mimetic compound (SMC), SW IV-52s, to form SW III-123. The delivery function of the sigma-2 moiety and cell killing mechanisms of SW III-123 were examined in human ovarian cancer cell lines.
SW III-123 internalisation into ovarian cancer cells was mediated by sigma-2 receptors. SW III-123, but not SW IV-52s or SW 43, exhibited potent cytotoxicity in human ovarian cancer cell lines SKOV-3, CaOV-3 and BG-1 after 24-h treatment, suggesting that the sigma-2 ligand successfully delivered SMC into ovarian cancer cells. SW III-123 induced rapid degradation of inhibitor of apoptosis proteins (cIAP1 and cIAP2), accumulation of NF-κB-inducing kinase (NIK) and phosphorylation of NF-κB p65, suggesting that SW III-123 activated both canonical and noncanonical NF-κB pathways in SKOV-3 cells. SW III-123 cleaved caspase-8, -9 and -3. Tumour necrosis factor alpha (TNFα) antibody markedly blocked SW III-123-induced cell death and caspase-3 activity in SKOV-3 cells, indicating that SW III-123 activated both intrinsic and extrinsic apoptotic pathways and induced TNFα-dependent cell death in SKOV-3 cells.
Sigma-2 ligands are a promising tumour-targeting drug delivery agent. Sigma-2-conjugated SMC exemplifies a novel class of therapeutic drugs for treating ovarian cancer.
sigma-2 受体已被验证为增殖肿瘤的生物标志物。第二线粒体衍生的半胱天冬酶激活剂（Smac）是一种从线粒体释放到细胞质中的蛋白质，导致细胞凋亡。在这项研究中，我们研究了一种 sigma-2 配体作为治疗卵巢癌的肿瘤靶向药物递送剂。
sigma-2 配体 SW43 与 Smac 模拟物（SMC）SWIV-52s 缀合形成 SWIII-123。sigma-2 部分的递送功能和 SWIII-123 的细胞杀伤机制在人卵巢癌细胞系中进行了研究。
SWIII-123 被 sigma-2 受体介导内化进入卵巢癌细胞。SWIII-123 而非 SWIV-52s 或 SW43 在 24 小时处理后在人卵巢癌细胞系 SKOV-3、CaOV-3 和 BG-1 中表现出强大的细胞毒性，表明 sigma-2 配体成功地将 SMC 递送到卵巢癌细胞中。SWIII-123 诱导凋亡蛋白抑制剂（cIAP1 和 cIAP2）的快速降解、NF-κB 诱导激酶（NIK）的积累和 NF-κB p65 的磷酸化，表明 SWIII-123 在 SKOV-3 细胞中激活了经典和非经典 NF-κB 途径。SWIII-123 切割半胱天冬酶-8、-9 和 -3。肿瘤坏死因子α（TNFα）抗体显著阻断 SWIII-123 在 SKOV-3 细胞中诱导的细胞死亡和 caspase-3 活性，表明 SWIII-123 激活了内在和外在凋亡途径，并诱导 SKOV-3 细胞中 TNFα 依赖性细胞死亡。
sigma-2 配体是一种有前途的肿瘤靶向药物递送剂。sigma-2 缀合的 SMC 是治疗卵巢癌的一类新型治疗药物。
Zotero 插件
