Sorafenib Plus Valproic Acid for Infant Spinal Glioblastoma

Rokes, Christopher; Remke, Marc; Guha-Thakurta, Nandita; Witt, Olaf; Korshunov, Andrey; Pfister, S. M.; Wolff, Johannes

doi:10.1097/mph.0b013e3181d74702

Cited by 12 publications

(8 citation statements)

References 23 publications

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“…Valproic acid exhibits anticancer potential through causing cell growth arrest, differentiation, autophagy, and apoptosis. In addition, it resensitizes cancer cells to treatment by conventional antineoplastic agents , . Moreover, valproic acid also exerts cytoprotective effects and suppresses apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Valproic acid sensitizes human glioma cells to gefitinib‐induced autophagy

Chang

et al. 2015

IUBMB Life

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Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long-term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), and degradation of p62. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 but not broad-spectrum caspase inhibitor attenuated gefitinib/valproic acid-induced growth inhibition. Gefitinib/valproic acid-induced autophagy was accompanied by the activation of liver kinase-B1 (LKB1)/AMP-activated protein kinase (AMPK)/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib/valproic acid-induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib/valproic acid increased intracellular reactive oxygen species generation and N-acetyl cysteine attenuated gefitinib/valproic acid-caused autophagy and growth inhibition. In addition to demonstrating the autophagic mechanisms of gefitinib/valproic acid, the results of this study further suggest that intracellular oxidative stress and the LKB1/AMPK signaling might be a potential target for the development of therapeutic strategy against glioma.

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Section: Discussionmentioning

confidence: 99%

Valproic acid sensitizes human glioma cells to gefitinib‐induced autophagy

Chang

et al. 2015

IUBMB Life

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“…the use of therapeutic agents which act upon inhibit growth factor receptors; receptors present both on the glioma cell and the tumor endothelial cells. 29,30 However, no Phase I trial as yet has shown a highly significant prolongation of patient survival using novel signal modulatory drugs. We performed animal studies using an invasive GBM isolate which expresses the constitutively active form of the EGF receptor (ERBB1 vIII).…”

Section: Discussionmentioning

confidence: 99%

OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing

Booth

Cazanave

Hamed

et al. 2012

Cancer Biology & Therapy

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We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills tumor cells. OSU lethality was suppressed by knock down of PERK and enhanced by knock down of ATF6 and IRE1α. OSU treatment suppressed expression of the chaperone, BiP/GRP78, and did so through reduced stability of the protein. Knock down of BiP/GRP78 further enhanced OSU lethality. Overexpression of BiP/GRP78 abolished OSU toxicity. Pre-treatment of cells with OSU enhanced radiosensitivity to a greater extent than concomitant or sequential drug treatment with radiation exposure. Expression of a mutant active p110 PI3K, or mutant active forms of the EGFR in GBM cells did not differentially suppress OSU killing. In contrast loss of PTEN function reduced OSU lethality, without altering AKT, p70 S6K or mTOR activity, or the drug's ability to radiosensitize GBM cells. Knock down of PTEN protected cells from OSU and radiation treatment whereas re-expression of PTEN facilitated drug lethality and radiosensitization. In a dose-dependent fashion OSU prolonged the survival of mice carrying GBM tumors and interacted with radiotherapy to further prolong survival. Collectively, our data show that reduced BiP/GRP78 levels play a key role in OSU-3012 toxicity in GBM cells, and that this drug has in vivo activity against an invasive primary human GBM isolate.

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“…Prognostic significance of the KIAA1549:BRAF fusion, if any, is still unclear, although a few studies have found no differences in survival between tumors with and without BRAF duplication/fusion (28, 42, 45, 48). Nevertheless, the frequent BRAF alteration in PA I may serve as a novel therapeutic target for pharmacological inhibition of the MAPK pathway, particularly in tumors that are difficult to fully excise surgically (75, 78, 88). Previous in vitro studies have revealed that stable silencing of BRAF through lentiviral transduction with inhibition of Map/Erk kinase (MEK)1/2 blocked proliferation and arrested growth of glioma cells (73).…”

Section: Braf Fusionsmentioning

confidence: 99%

The Next Generation of Glioma Biomarkers: MGMT Methylation, BRAF Fusions and IDH1 Mutations

Deimling¹,

Korshunov²,

Hartmann³

2010

Brain Pathology

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159

115

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For some, glioma biomarkers have been expected to solve common diagnostic problems in routine neuropathology service caused by insufficient material, technical shortcomings or lack of experience. Further, biomarkers should predict patient outcome and direct optimal therapy for the individual patient. Unfortunately, current biomarkers still fall somewhat short of these grand expectations. While there has been some progress, it has generally been slow and in small steps. In this review, the newest set of glioma biomarkers: O(6) -methylguanine-DNA methyltransferase (MGMT) methylation, BRAF fusion and IDH1 mutation are discussed. MGMT methylation is well established as a prognostic/predictive marker for glioblastoma; however, technical questions regarding testing remain, it is not currently utilized widely in guiding patient management, and it has proven to be of no assistance in diagnostics. In contrast, BRAF fusion and IDH1 mutation analyses promise to be very helpful for classifying and grading gliomas, while their potential predictive value has yet to be established.

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Sorafenib Plus Valproic Acid for Infant Spinal Glioblastoma

Cited by 12 publications

References 23 publications

Valproic acid sensitizes human glioma cells to gefitinib‐induced autophagy

Valproic acid sensitizes human glioma cells to gefitinib‐induced autophagy

OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing

The Next Generation of Glioma Biomarkers: MGMT Methylation, BRAF Fusions and IDH1 Mutations

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