Antisense Inhibition of Survivin Expression as a Cancer Therapeutic
Antisense Inhibition of Survivin Expression as a Cancer Therapeutic
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DOI：
10.1158/1535-7163.mct-10-0756
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发表时间：
2011-02-01
影响因子：
5.7
通讯作者：
Patel, Bharvin K. R.
中科院分区：
文献类型：
--
作者：
Carrasco, Rosa A.;Stamm, Nancy B.;Patel, Bharvin K. R.
存活素是凋亡抑制蛋白家族的一员，在有丝分裂过程中以细胞周期依赖的方式表达，并定位于有丝分裂器的不同组分，在细胞分裂和抑制凋亡中起重要作用。生存素在绝大多数人类癌症中表达，但在正常成人组织中不表达。Survivin的表达通常与多种癌症患者的不良预后相关。这些特征使得生存素成为一个有吸引力的靶点，可以针对其开发癌症治疗剂。我们已经鉴定了一种生存素反义寡核苷酸（阿索），其通过定量RT-PCR和免疫印迹分析测定，有效下调来自肺、结肠、胰腺、肝、乳腺、前列腺、卵巢、宫颈、皮肤和脑的人癌细胞中生存素的表达。该阿索（LY 2181308）特异性抑制多种癌细胞系中的生存素表达，诱导caspase-3依赖性凋亡、细胞周期停滞在G（2）-M期和多核细胞。我们还发现，抑制生存素的表达LY 2181308敏感的肿瘤细胞化疗诱导的凋亡。最重要的是，在体内人异种移植肿瘤模型中，与盐水或其序列特异性对照寡核苷酸相比，LY 2181308产生显著的抗肿瘤活性，并对吉西他滨、紫杉醇和多西他赛致敏。此外，我们发现这种抗肿瘤活性与这些异种移植肿瘤中生存素表达的显著抑制有关。在此基础上，正在临床环境（II期）中评估LY 2181308与多西他赛联合治疗前列腺癌的效果。Mol Cancer Ther; 10（2）; 221-32.（C）2011年《非洲标准化评论》。
Survivin, a family member of the inhibitor of apoptosis proteins that is expressed during mitosis in a cell cycle-dependent manner and localized to different components of the mitotic apparatus, plays an important role in both cell division and inhibition of apoptosis. Survivin is expressed in a vast majority of human cancers, but not in normal adult tissues. Survivin expression is often correlated with poor prognosis in a wide variety of cancer patients. These features make survivin an attractive target against which cancer therapeutics could be developed. We have identified a survivin antisense oligonucleotide (ASO) that potently downregulated survivin expression in human cancer cells derived from lung, colon, pancreas, liver, breast, prostate, ovary, cervix, skin, and brain as measured by quantitative RT-PCR and immunoblotting analysis. Specific inhibition of survivin expression in multiple cancer cell lines by this ASO (LY2181308) induced caspase-3-dependent apoptosis, cell cycle arrest in the G(2)-M phase, and multinucleated cells. We also showed that inhibition of survivin expression by LY2181308 sensitized tumor cells to chemotherapeutic-induced apoptosis. Most importantly, in an in vivo human xenograft tumor model, LY2181308 produced significant antitumor activity as compared with saline or its sequence-specific control oligonucleotide and sensitized to gemcitabine, paclitaxel, and docetaxel. Furthermore, we showed that this antitumor activity was associated with significant inhibition of survivin expression in these xenograft tumors. On the basis of these, LY2181308 is being evaluated in a clinical setting (Phase II) in combination with docetaxel for the treatment of prostate cancer. Mol Cancer Ther; 10(2); 221-32. (C)2011 AACR.