生存素抵消微管de-stabilizers的疗效稳定微管蛋白聚合体。

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张CH,陈HH,郭CC马廉亭,Coumar女士,谢长廷惠普,Chang司法院

生存素抵消微管de-stabilizers的疗效稳定微管蛋白聚合体。

摩尔癌症。2009年7月3日,8:43。doi: 10.1186 / 1476-4598-8-43。

PubMed ID

19575780 (在PubMed

]

文摘

背景:生存素是一种双功能蛋白。还存在它能抑制细胞的凋亡抑制,并促进细胞生长稳定微管在有丝分裂。生存素已被证实能诱导耐药性的表达各种化学治疗药物如顺铂(DNA损伤剂)和紫杉醇(微管稳定剂)的癌症。然而,survivin-induced抗微管de-stabilizers如长春花生物碱和Combretastatin 4 (CA-4) -相关化合物很少展示了过去。此外,问题是是否存活素起着主导作用的处理还存在胞质分裂或抑制活性在细胞治疗anti-mitotic化合物。本研究的目的是评估的影响生存素在人类癌症细胞微管的阻力和易感性de-stabilizer-induced细胞死亡。结果:BPR0L075 CA-4模拟,诱导微管de-polymerization和随后caspase-dependent细胞凋亡。研究之间的关系的表达生存素和抗微管de-stabilizers一KB-derived BPR0L075-resistant癌症细胞系,KB-L30,生成研究。在这里,我们发现生存素在KB-L30细胞过度。下调小干扰rna诱导生存素的过度敏感,敏感的癌细胞和部分re-stored BPR0L075 BPR0L075 KB-L30细胞。 Western blot analysis revealed that down-regulation of survivin induced microtubule de-stabilization in both KB and KB-L30 cells. However, the same treatment did not enhance the down-stream caspase-3/-7 activities in BPR0L075-treated KB cells. Translocation of a caspase-independent apoptosis-related molecule, apoptosis-inducing factor (AIF), from cytoplasm to the nucleus was observed in survivin-targeted KB cells under BPR0L075 treatment. CONCLUSION: In this study, survivin plays an important role in the stability of microtubules, but not with caspases inhibition. Over-expression of survivin counteracts the therapeutic effect of microtubule de-stabilizer BPR0L075 probably by stabilizing tubulin polymers, instead of the inhibition of caspase activity in cancer cells. Besides microtubule-related caspase-dependent cell death, caspase-independent mitotic cell death could be initiated in survivin/BPR0L075 combination treatments. We suggest that combining microtubule de-stabilizers with a survivin inhibitor may attribute to a better clinical outcome than the use of anti-mitotic monotherapy in clinical situations.

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药物靶点

药物	目标	类	生物	药理作用	行动
紫杉醇	微管蛋白beta 1链	蛋白质	人类	是的	抑制剂	细节