Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma

Weller, Michael; Gorlia, Thierry; Jg, Cairncross; Bent, Martin J. van den; Mason, Warren P.; Bélanger, Karl; Brandes, Alba A.; Bogdahn, Ulrich; Macdonald, David R.; Forsyth, Peter; Rossetti, Andrea O.; Lacombe, Denis; Mirimanoff, R.O.; Vecht, Charles J.; Stupp, Roger

doi:10.1212/wnl.0b013e31822f02e1

Cited by 262 publications

(196 citation statements)

References 21 publications

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“…P4HB inhibition was identified as an effective method in combination with TMZ for the treatment of TMZ-resistant GBM (35). valparaiso acid can regulate the effectiveness of TMZ-radiochemotherapy and prolong overall survival in patients with newly diagnosed GBM (36). GBM is considered as a heterogeneous group of tumors with differing cellular lineages, genetic alteration, biological behavior and response to chemotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Lan

Yang

Han

et al. 2015

International Journal of Oncology

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Abstract. The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC 50 ) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC 50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Lan

Yang

Han

et al. 2015

International Journal of Oncology

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“…The use of low-dose HDAC inhibitors as a novel therapeutic approach warrants further investigation. 118 Panobinostat, 119120 and other HDAC inhibitors, including vorinostat, 121 belinostat, romidepsin 122 and valproate 123,124 (reviewed in 125 ), are currently been used in clinical trials for patients with brain tumors (Table 2). …”

Section: Histone Acetyltransferases and Deacetylasesmentioning

confidence: 99%

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Maury

Hashizume

2017

Epigenetics

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Malignancies are characterized by the reprogramming of epigenetic patterns. This reprogramming includes gains or losses in DNA methylation and disruption of normal patterns of covalent histone modifications, which are associated with changes in chromatin remodeling processes. This review will focus on the mechanisms underlying this reprogramming and, specifically, on the role of histone modification in chromatin machinery and the modifications in epigenetic processes occurring in brain cancer, with a specific focus on epigenetic therapies for pediatric brain tumors.

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“…The authors of this study reasoned that the improvement of in treatment results in the arm with VPA was due to the inhibition of HDAC (ref. 90 ). VPA with doxorubicin appeared to be an effective chemotherapy regimen (16% response rate) in patients with refractory or recurrent mesothelioma 91 .…”

Section: Clinical Studies and Registered Drugsmentioning

confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma

Cited by 262 publications

References 21 publications

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Histone deacetylase inhibitors in cancer therapy. A review

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