Tubulins as therapeutic targets in cancer: from bench to bedside

0387835 - ÚMG 2013 RIV GB eng J - Článek v odborném periodiku
Katsetos, C.D. - Dráber, Pavel
Tubulins as therapeutic targets in cancer: from bench to bedside.
Current Pharmaceutical Design. Roč. 18, č. 19 (2012), s. 2778-2792. ISSN 1381-6128. E-ISSN 1873-4286
Grant CEP: GA ČR GA204/09/1777; GA AV ČR KAN200520701; GA MŠMT 1M0506
Výzkumný záměr: CEZ:AV0Z50520514
Klíčová slova: microtubules * tubulin * cancer
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 3.311, rok: 2012

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 alpha beta-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 beta-tubulin isotypes, posttranslational modifications of tubulin dimers, gamma-tubulin and microtubule nucleation, and microtubule regulatory proteins. Emphasis is placed on the overexpression of (i) the beta III isotype, which functions as a survival factor associated with dynamic instability of microtubules; (ii) gamma-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 III-tubulin in resistance of cancer cells to taxanes is examined. Attention is called to the novel concept that III-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.
Trvalý link: http://hdl.handle.net/11104/0218615