University of Glasgow, Institute of Cancer Sciences, Beatson Laboratories, Bearsden, Glasgow, UK.
J Cell Mol Med. 2011 Feb;15(2):179-86. doi: 10.1111/j.1582-4934.2010.01253.x.
Aberrant telomere homeostasis is essential for cell immortality, enabling cells to evade telomere dependent senescence. Disruption of telomere structure and function in cancer cells is highly toxic as shown by detailed pre-clinical evaluation of telomerase inhibitors. Under telomerase inhibition, cells must divide sufficiently frequently to allow one or more telomeres to shorten to an unprotected length. Functioning telomeres are disguised from the DNA damage machinery by DNA remodelling and other activities of the telomere binding complex shelterin. Direct interference with shelterin has been shown to result in cell killing and small molecules directly targeting telomere DNA also have anti-tumour effects partially dependent on shelterin disruption. However, shelterin components have not generally been regarded as therapeutic targets in their own right. In this review, we explore the possibilities for therapeutic targeting of the shelterin complex.
端粒稳态的异常对细胞的永生化至关重要，使细胞能够逃避端粒依赖性衰老。端粒酶抑制剂的详细临床前评估表明，癌细胞中端粒结构和功能的破坏具有高度的毒性。在端粒酶抑制下，细胞必须足够频繁地分裂，以使一个或多个端粒缩短到无保护的长度。端粒结合复合物庇护素的 DNA 重塑和其他活性使功能端粒免受 DNA 损伤机制的影响。已经证明，直接干扰庇护素会导致细胞死亡，而直接靶向端粒 DNA 的小分子也具有抗肿瘤作用，部分依赖于庇护素的破坏。然而，庇护素成分通常并未被视为其自身的治疗靶点。在这篇综述中，我们探讨了靶向庇护素复合物的治疗可能性。
