Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Abstract

Background/Aims: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug is used to treat epileptic seizure of glioblastoma patients. Besides its antiepileptic activity, VPA has been attributed further functions that improve the clinical outcome of glioblastoma patients. Those comprise the inhibition of some histone deacetylase (HDAC) isoforms which reportedly may result in radiosensitization. Retrospective analysis of patient data, however, could not unequivocally confirm a prolonged survival of glioblastoma patients receiving VPA. The present study aimed to identify potential VPA targets at the cellular level. Methods: To this end, the effect of VPA on metabolism, Ca²⁺-, biochemical and electro-signaling, cell-cycling, clonogenic survival and transfilter migration was analyzed in three human glioblastoma lines (T98G, U-87MG, U251) by MTT assay, Ca²⁺ imaging, immunoblotting, patch-clamp recording, flow cytometry, delayed plating colony formation and modified Boyden chamber assays, respectively. In addition, the effect of VPA on clonogenic survival of primary glioblastoma spheroid cultures treated with temozolomide and fractionated radiation was assessed by limited dilution assay. Results: In 2 of 3 glioblastoma lines, clinical relevant concentrations of VPA slightly slowed down cell cycle progression and decreased clonogenic survival. Furthermore, VPA induced Ca²⁺ signaling which was accompanied by pronounced K⁺ channel activity and transfilter cell migration. VPA did not affect metabolic NAD(P)H formation or radioresistance of the glioblastoma lines. Finally, VPA did not impair clonogenic survival or radioresistance of temozolomide-treated primary spheroid cultures. Conclusions: Combined, our in vitro data do not propose a general use of VPA as a radiosensitizer in anti-glioblastoma therapy.

Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells

“…This can be explained with a higher negative physiological membrane potential in U251 as compared to T98G cells since the higher the physiological membrane potential the more positive clamp voltage is required to reach the activation voltage of the channel. Most importantly, K + selectivity, high unitary conductance, and voltage dependence of the TTFields-induced channel were identical to the characteristics of paxilline-sensitive BK K + channels reported earlier to be highly expressed in T98G and U251 cells [45].…”

“…Taking into account that cell cycle [57], cell migration [38,45,57], brain infiltration [40], cell death programming [57], DNA repair and radioresistance [42,57] of glioblastoma cells have been demonstrated to be regulated by Ca 2+ -dependent signaling pathways [58] an interference of TTFields with glioblastoma biology can be expected. In line with this assumption, the present study demonstrated that TTFields indeed interfered with all cell biological parameters tested.…”

AMPA receptor antagonist perampanel affects glioblastoma cell growth and glutamate release in vitro

“…In line with our observation, Eckert et al . 2017 showed that VPA had only small anti-proliferative effects on human GBM cell lines, but the authors were unable to detect an impairment of survival or a lower radioresistance of temozolomide-treated primary spheroid cultures [46]. When used in dose escalation experiments that excess patient plasma levels [5], one may find inhibitory effects by VPA [47–50].…”

EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

“…The molecular biology of GBM is highly heterogeneous. Despite advances in the technical proficiencies of surgical and radiation oncology, patients with GBM have a poor prognosis, with a median survival of less than one year from the time of diagnosis and a five-year mortality of over 95% [5][6][7]. To date, the pathogenesis of GBM is still poorly understood.…”