Targeting βIII-Tubulin in Glioblastoma Multiforme: From Cell Biology and Histopathology to Cancer Therapeutics

Christos      D. Katsetos; Pavel      Draber; Maria      Kavallaris

doi:10.2174/187152011797378760

Abstract

Glioblastoma multiforme (GBM) is the most common, aggressive, and chemorefractory brain tumor in human adults. Notwithstanding significant discoveries in the elucidation of pathways of molecular signaling and genetics of GBM during the past 20 years there has been no breakthrough in the pharmacological treatment of this high-grade malignancy. We, and others, have previously demonstrated increased expression of βIII-tubulin in GBM asserting a link between aberrant expression of this β-tubulin isotype and a disruption of microtubule dynamics associated either with malignant tumor development de novo, or with progression and malignant transformation of a low-grade glioma into GBM. This article reviews βIII-tubulin as a promising target in the experimental treatment of GBM and examines the potential use of epothilones, a new family of anticancer agents shown to be active in βIII-tubulin-expressing tumor cells, as well as the “double hit” therapeutic concept of tumor cell sensitization to tubulin binding agents (TBAs) by βIII-tubulin silencing. The latest progress regarding the function and potential role of βIII-tubulin in aggressive tumor behavior, cancer stem cells, tumor cell hypoxia, and resistance to taxane-related compounds, is also critically appraised.

Keywords: Tubulin, glioblastoma multiforme, TBA, tubulin binding agent(s), epothilones, class III beta-tubulin, microtubule, microtubule-associated proteins (MAPs), posttranslational modifications, gliotypic neural stem cells