Department of Pediatrics, Drexel University College of Medicine, St. Christopher's Hospital for Children, 3601 A Street, Philadelphia, PA 19134, USA.
Curr Pharm Des. 2012;18(19):2778-92. doi: 10.2174/138161212800626193.
Tubulin is the target of some of the most widely used and time-honored anticancer tubulin-binding agents (TBAs). The clinical usefulness of many TBAs has been held back as a result of tumor cell drug-resistance. The elucidation of the three-dimensional structure of αβ-tubulin dimer has provided an opportunity for rational drug design aimed at generating compounds that will target tubulin in therapeutically more efficacious ways compared to presently available drugs. An issue to be addressed is which one(s) of the tubulin species, their isotypes, or their posttranslationally modified forms, should be specifically targeted in cancer chemotherapy. This review offers a critical appraisal of current knowledge on tubulins in cancer and an update on new anti-neoplastic microtubule-targeted treatment strategies. Specifically, it examines, across disciplines, cellular/molecular, biochemical, clinical/pathological, and pharmacological aspects of β-tubulin isotypes, posttranslational modifications of tubulin dimers, γ-tubulin and microtubule nucleation, and microtubule regulatory proteins. Emphasis is placed on the overexpression of (i) the βIII isotype, which functions as a survival factor associated with dynamic instability of microtubules; (ii) γ-tubulin, a key microtubule nucleating protein; and (iii) the microtubule severing enzyme spastin, involved in cell motility and proliferation of glioblastoma cells. The role of βIII-tubulin in resistance of cancer cells to taxanes is examined. Attention is called to the novel concept that βIII-tubulin functions as a "gateway" for prosurvival signals in partnership with GTPases, such as GBP1. Appraisal is also offered on epothilones and the concept of hypersensitization to TBAs as promising therapeutic strategies in taxane resistant epithelial cancers and in high-grade gliomas.
微管蛋白是一些最广泛使用和历史悠久的抗癌微管结合剂 (TBA) 的靶标。由于肿瘤细胞耐药性，许多 TBA 的临床应用受到限制。αβ-微管蛋白二聚体的三维结构阐明为合理药物设计提供了机会，旨在生成比现有药物更有效地靶向微管蛋白的化合物。需要解决的问题是，应该针对癌症化疗中的哪种（些）微管蛋白物种、它们的同工型或翻译后修饰形式。这篇综述批判性地评价了癌症中微管蛋白的现有知识，并更新了新的抗瘤微管靶向治疗策略。具体而言，它跨学科地检查了β-微管蛋白同工型、微管蛋白二聚体的翻译后修饰、γ-微管蛋白和微管核形成以及微管调节蛋白的细胞/分子、生化、临床/病理和药理学方面。重点放在（i）βIII 同工型的过表达上，它作为与微管动态不稳定性相关的存活因子起作用；（ii）γ-微管蛋白，一种关键的微管核形成蛋白；（iii）微管切割酶 spastin，涉及神经胶质瘤细胞的运动和增殖。研究了βIII-微管蛋白在癌症细胞对紫杉烷耐药中的作用。提请注意一个新的概念，即βIII-微管蛋白与 GTPases（如 GBP1）一起作为促进存活信号的“门户”发挥作用。还评估了埃坡霉素和 TBA 超敏化作为有前途的治疗策略在紫杉烷耐药上皮癌和高级别神经胶质瘤中的作用。
