Paclitaxel-resistant细胞突变beta-tubulin paclitaxel-binding地区(Asp26Glu)和不稳定的微管。
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哈里米,Loganzo F, Annable T,谭X,周报,穆Morilla DB,荨麻JH,斯奈德JP,格林伯格LM
Paclitaxel-resistant细胞突变beta-tubulin paclitaxel-binding地区(Asp26Glu)和不稳定的微管。
摩尔癌症。”2006年2月,5 (2):270 - 8。
- PubMed ID
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16505100 (在PubMed]
- 文摘
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抵抗paclitaxel-based治疗是临床中经常遇到。内在或获得性耐紫杉醇机制不清楚。我们试图描述的耐药机制发展癌症细胞系慢性接触紫杉醇在22逆转剂的存在,cl - 347099。表皮样瘤行KB-3-1被暴露在增加浓度的紫杉醇和5 micromol / L cl - 347099 1年。细胞生长在15 nmol / L紫杉醇+ cl - 347099 (KB-15-PTX / 099)开发18倍耐紫杉醇最大增长依赖于紫杉醇。他们生长良好,保留耐紫杉醇在无胸腺的老鼠。抗力移转(3 - 5倍)组织培养中观察到多烯紫杉醇,这部小说紫杉烷mac - 321 b和epothilone抵押品敏感性(约三倍)观察解聚剂长春花碱,dolastatin-10, hti - 286。KB-15-PTX / 099 -耐药细胞没有过多表达22他们也没有改变[14 c]紫杉醇的积累与亲代细胞。然而,一个新颖的点突变(T)导致谷氨酸Asp26替换在课堂上我(M40) beta-tubulin被发现。基于电子晶体学结构Zn-stabilized微管蛋白表,苯基环颈的NHCO-C6H5紫杉醇的接触Asp26 beta-tubulin,暗示ligand-induced突变。 Optimized model complexes of paclitaxel, docetaxel, and MAC-321 in beta-tubulin show a novel hydrogen bonding pattern for the glutamate mutant and rationalize the observed resistance profiles. However, a mutation in the paclitaxel binding pocket does not explain the phenotype completely. KB-15-PTX/099 cells have impaired microtubule stability as determined by a reduced percentage of tubulin in microtubules and reflected by less acetylated tubulin. These results suggest that a mutation in tubulin might affect microtubule stability as well as drug binding and contribute to the observed resistance profile.