SPC3042:: a proapoptotic survivin inhibitor
SPC3042:: a proapoptotic survivin inhibitor
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DOI：
10.1158/1535-7163.mct-08-0161
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发表时间：
2008-09-01
影响因子：
5.7
通讯作者：
Koch, Troels
中科院分区：
文献类型：
--
作者：
Hansen, Jens Bo;Fisker, Niels;Koch, Troels
通过严格控制细胞凋亡和细胞分裂来调节高等生物体的细胞内稳态的能力对于生命至关重要。这些机制的失调通常与细胞中的癌性表型相关。最佳的癌症治疗是在有效杀死癌细胞和同时最小化或避免对周围健康组织的损害之间的良好平衡。为了实现这一点，有必要识别和抑制癌细胞强烈依赖的分子靶标。存活素代表这样的靶点，并且先前已经公开了肽疫苗、小分子YM 155和反义分子LY 2181308/ISIS 23722通过不同的机制被用作存活素抑制剂。本文介绍了一种新的survivin反义抑制剂SPC 3042，并与已发表的反义药物LY 2181308/ISIS 23722进行了比较。SPC 3042是16-mer锁核酸（LNA）寡核苷酸，并且被设计为在侧翼中含有7个LNA核苷酸的完全硫代磷酸化的gapmer。与早期的反义试剂相比，SPC 3042中的LNA核苷酸提供了核酸酶稳定性和更高的存活素mRNA抑制效力。结果表明，SPC 3042下调生存素导致细胞周期停滞，明显的细胞凋亡和Bcl-2的下调。体外和体内研究表明，SPC 3042对紫杉醇治疗前列腺癌细胞有增敏作用。
The ability to regulate the cellular homeostasis of a higher organism through tight control of apoptosis and cell division is crucial for life. Dysregulation of these mechanisms is often associated with cancerous phenotypes in cells. Optimal cancer therapy is a fine balance between effective cancer cell killing and at the same time minimizing, or avoiding, damage to the surrounding healthy tissue. To obtain this, it is necessary to identify and inhibit molecular targets on which the cancer cells are strongly dependent. Survivin represents such a target, and it has been published previously that peptide vaccines, the small-molecule YM155, and the antisense molecule LY2181308/ISIS23722, via different mechanisms, have been used as survivin inhibitors. In this article, a new potent antisense inhibitor of survivin, SPC3042, is presented, and the properties of SPC3042 are compared with the previously published antisense drug, LY2181308/ISIS23722. SPC3042 is a 16-mer locked nucleic acid (LNA) oligonucleotide and designed as a fully phosphorothiolated gapmer containing 7 LNA nucleotides in the flanks. The LNA nucleotides in SPC3042 provide nuclease stability and higher potency for survivin mRNA inhibition compared with earlier generations of antisense reagents. It is shown that the down-regulation of survivin with SPC3042 leads to cell cycle arrest, pronounced cellular apoptosis, and down-regulation of Bcl-2. It is also shown that SPC3042 is a sensitizer of prostate cancer cells to Taxol treatment in vitro and in vivo.