Epigenetic targeting of glioma stem cells: Short-term and long-term treatments with valproic acid modulate DNA methylation and differentiation behavior, but not temozolomide sensitivity

Riva, Gabriele; Butta, Valentina; Cilibrasi, Chiara; Baronchelli, Simona; Redaelli, Serena; Dalprà, Leda; Lavitrano, Marialuisa; Bentivegna, Angela

doi:10.3892/or.2016.4665

Cited by 23 publications

(33 citation statements)

References 57 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were unexpected in light of the reported chromatin remodeling action of VPA [18, 48-50] and contradictory to previous in vitro studies [10-15, 17, 48, 51, 52] which clearly show VPA-induced cell death or radio- or chemosensitization in cancer cells including glioma. Unlike the present work, VPA concentrations of 1-5 mM [52], 1.5-2 mM [10], 1-5 mM [51], 2.5-5 mM [11], 1.5-3 mM [12], 1-15 mM [13], 2-16 mM [14], 7.5 mM [18], 2 mM [19], 5-20 mM [53], 1-10 mM [21], or 4.8 mM [22] were applied in these studies.…”

Section: Discussionmentioning

confidence: 44%

“…DNA demethylation, however, might induce up-regulation of MGMT expression and might confer resistance to temozolomide. In contrast to this assumption, VPA has been shown to down-regulate MGMT expression in glioma cells [17] and to sensitize glioblastoma cells to temozolomide in vitro in some [11, 17, 18] but not all [19] studies (for review see [20]. …”

Section: Introductionmentioning

confidence: 99%

“…Beyond radio- and temozolomide sensitization, VPA-mediated histone hyperacetylation and DNA demethylation are associated with changes in cell morphology, decrease cell viability and increase apoptosis rates [14, 19, 21, 22]. Moreover, VPA treatment of glioma cells has been demonstrated to boost the adaptive immune response.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Eckert

Klumpp

Huber

2017

Cell Physiol Biochem

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 44%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Eckert

Klumpp

Huber

2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…The prodifferentiating ability of Pio was evaluated through the expression analysis of selected stemness (CD133 and Nestin) and differentiation markers (GFAP, β III tubulin, and MBP) that had been previously used in the literature [ 3 , 18 , 22 , 23 ], comparing cells untreated or treated with Pio 10 μ M, the minimal effective concentration, for 72 hs. Representative images are reported in Figure 5 .…”

Section: Resultsmentioning

confidence: 99%

Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?

et al. 2016

Self Cite

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) represents one of the most frequent malignant brain tumors. Current therapies do not provide real solutions to this pathology. Their failure can be ascribed to a cell subpopulation with stem-like properties called glioma stem cells (GSCs). Therefore, new therapeutic strategies GSC-targeted are needed. PPARγ, a nuclear receptor involved in lipid metabolism, has already been indicated as a promising target for antineoplastic therapies. Recent studies have reported that synthetic PPARγ agonists, already in clinical use for the treatment of type II diabetes, exhibit antineoplastic effects in a wide range of malignant tumor cells, including glioma cells. We investigated the effect of the synthetic PPARγ agonist Pioglitazone on viability, proliferation, morphology, and differentiation in six GSC lines isolated from GBM patients. We also analyzed Pioglitazone-induced changes in transcriptional levels of Wnt/β catenin related genes. Results showed that response to Pioglitazone was heterogeneous inducing an evident decrease of cell viability and proliferation only in a subset of GSC lines. We did not find any sign of cell differentiation neither observing cell morphology nor analyzing the expression of stemness and differentiation markers. Moreover, Wnt/β signaling pathway was only mildly affected from a transcriptional point of view after Pioglitazone exposure.

show abstract

“…However, a small number of studies are available on the interaction of VPA and alkylating agents and the effects of VPA on chemotherapy for glioma ( 16 ), particularly for the association of VPA and initiation and recurrence of glioma. The present study used GSCs as the target to explore whether VPA affected the susceptibility of human glioma cells for TMZ and ACNU in vitro , and its effects on the MGMT promoter methylation and its expression of MGMT in glioma cells.…”

Section: Introductionmentioning

confidence: 99%

Effects of valproic acid on the susceptibility of human glioma stem cells for TMZ and ACNU

Xia²,

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

To investigate the effect of valproic acid (VPA) on the susceptibility of glioma stem cells to temozolomide (TMZ) and nimustine (ACNU), the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and its expression of MGMT were examined. A total of 3 glioma cell populations were isolated from human glioma tissues, and immunocytochemistry was used to detect the expression of MGMT. VPA inhibition on the growth of the 3 glioma cell populations exposed to various concentrations of TMZ and ACNU was evaluated. Flow cytometry was applied to detect the apoptosis of glioma cells, and a methylation-specific polymerase chain reaction was used to identify methylation of MGMT promoter. Immunocytochemistry results indicated that MGMT was negatively expressed in the G1 population, but positively expressed in the G2 and G3 populations. Cell growth inhibition assays demonstrated that the survival rate in the VPA + TMZ or ACNU groups was decreased compared with that of the TMZ or ACNU alone groups (P<0.05). As for the apoptotic rate, those in the VPA alone group were increased compared with the control group (P<0.05), and the rates in the VPA + TMZ or ACNU groups were increased compared with TMZ or ACNU alone groups (P<0.05). The expression of MGMT remained negative in the G1 population following treatment with VPA, but MGMT expression became negative in the 2 MGMT-positive cell populations (G2 and G3) following VPA treatment. The MGMT promoter in the G1 population was partially methylated in the control group, but was fully methylated following VPA treatment, while the promoters of G2, G3 were unmethylated in the control group and became partially methylated in the VPA treatment group. Taken together, TMZ and ACNU may suppress the growth of glioma stem cells in vitro in a dose-dependent manner. VPA may enhance the inhibitory effects of various concentrations of TMZ and ACNU on the growth of MGMT-negative/positive cells, particularly on MGMT-positive cell populations. VPA itself may induce the apoptosis of glioma cells, and VPA combined with TMZ or ACNU may enhance TMZ/ACNU-induced apoptosis of glioma stem cells. Furthermore, VPA may also promote the methylation of the MGMT promoter to silence MGMT expression in glioma cells, which may be an important mechanism through which VPA enhances the efficacy of TMZ and ACNU in targeting glioma stem cells.

show abstract

Epigenetic targeting of glioma stem cells: Short-term and long-term treatments with valproic acid modulate DNA methylation and differentiation behavior, but not temozolomide sensitivity

Cited by 23 publications

References 57 publications

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?

Effects of valproic acid on the susceptibility of human glioma stem cells for TMZ and ACNU

Contact Info

Product

Resources

About