Abstract
Glioblastoma multiform (GBM) is the most frequent primitive brain tumor with a high recurrence and mortality. Histone deacetylase inhibitors (HDACi) have evoked great interest because they are able to change transcriptomic profiles to promote tumor cell death but also induce side effects due to the lack of selectivity. We show in this paper new anticancer properties and mechanisms of action of low concentrations of vorinostat on various GBM cells which acts by affecting microtubule cytoskeleton in a non-histone 3 (H3) manner. Indeed, vorinostat induces tubulin acetylation and detyrosination, affects EB stabilizing cap on microtubule plus ends and suppresses microtubule dynamic instability. We previously identified EB1 overexpression as a marker of bad prognostic in GBM. Interestingly, we show for the first time to our knowledge, a strong decrease of EB1 expression in GBM cells by a drug. Altogether, our results suggest that low dose vorinostat, which is more selective for HDAC6 inhibition, could therefore represent an interesting therapeutic option for GBM especially in patients with EB1 overexpressing tumor with lower expected side effects. A validation of our hypothesis is needed during future clinical trials with this drug in GBM.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive brain tumor [1] with a median survival of approximately 14 months with treatment [2]
We show in this paper new anticancer properties and mechanisms of action of low concentrations of vorinostat on various GBM cells which acts by affecting microtubule cytoskeleton in a non-histone 3 (H3) manner
effective concentration (EC50) of vorinostat was decreased by 46% in End Biding protein 1 (EB1) overexpressing cells compared with control cells (4.16 ± 1.08 μM vs 7.70 ± 1.13 μM respectively)
Summary
Glioblastoma multiforme (GBM) is the most aggressive brain tumor [1] with a median survival of approximately 14 months with treatment [2]. Vorinostat, called SAHA (Suberanilo-hydroxamic acid), was approved by FDA in 2006 for human diseases like the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma It has showed anti-cancer activities like an up-regulation of the p21 tumor suppressor gene, G1 cell-cycle phase arrest [10] and tumor cell autophagy induction [11]. While the study was not conclusive for its primary efficacy end point, the authors found that vorinostat resistance and sensitivity signatures by RNA expression www.oncotarget.com profiling of baseline tumors, had a positive correlation with overall survival and progression free survival for a subgroup of patients [15] This strongly showed a real gain of vorinostat in some subpopulation. MT targeting agents (MTAs), which suppress MT dynamics [21, 22] are widely used for treatment of many human cancers
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