Tubulins as Therapeutic Targets in Cancer: from Bench to Bedside

Christos      D. Katsetos; Pavel      Draber

Abstract

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.

Keywords: Microtubules, tubulin, cancer, solid tumors, gliomas, beta-tubulin isotypes, gamma-tubulin, spastin, tubulin binding agent(s), epothilones