Regression of a glioblastoma multiforme: spontaneous versus a potential antineoplastic effect of dexamethasone and levetiracetam

Peddi, Prakash; Ajit, Nisha Elizabeth; Burton, Gary V.; El-Osta, Hazem

doi:10.1136/bcr-2016-217393

Cited by 11 publications

(10 citation statements)

References 23 publications

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“…Our results are supported by data reported by Kim et al demonstrating that the median progression-free survival and overall survival for patients who received LEV in combination with TMZ were significative longer than those for patients who did not receive LEV [ 48 ]. In addition, a case report was published by Peddi et al where a continuous regression of GBM was noted in a patient who received LEV and Dexamethasone without any cancer-targeted therapy, suggesting that the response may be related to Dexamethasone and/or LEV treatment [ 49 ]. Although more studies are needed to better evaluate the role of LEV and its molecular mechanism of action, these papers together with our results strongly suggest the beneficial effect of LEV as a chemosensitizer agent.…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis

et al. 2018

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BackgroundGlioblastoma multiforme (GBM) is a highly aggressive brain tumor in which cancer cells with stem cell-like features, called cancer stem cells (CSCs), were identified. Two CSC populations have been previously identified in GBM, one derived from the GBM area called enhanced lesion (GCSCs) and the other one from the brain area adjacent to the tumor margin (PCSCs) that greatly differ in their growth properties and tumor-initiating ability. To date the most effective chemotherapy to treat GBM is represented by alkylating agents such as temozolomide (TMZ), whose activity can be regulated by histone deacetylases (HDACs) inhibitors through the modulation of O6-methylguanine-DNA methyltransferase (MGMT) expression. Levetiracetam (LEV), a relatively new antiepileptic drug, modulates HDAC levels ultimately silencing MGMT, thus increasing TMZ effectiveness. However, an improvement in the therapeutic efficacy of TMZ is needed.MethodsCell proliferation was investigated by BrdU cell proliferation assay and by Western Blot analysis of PCNA expression. Apoptosis was evaluated by Western Blot and Immunofluorescence analysis of the cleaved Caspase-3 expression. MGMT and HDAC4 expression was analyzed by Western Blotting and Immunofluorescence. Statistical analysis was performed using the Student’s t test and Mann–Whitney test.ResultsHere we evaluated the effect of TMZ on the proliferation rate of the IDH-wildtype GCSCs and PCSCs derived from six patients, in comparison with the effects of other drugs such as etoposide, irinotecan and carboplatin. Our results demonstrated that TMZ was less effective compared to the other agents; hence, we verified the possibility to increase the effect of TMZ by combining it with LEV. Here we show that LEV enhances the effect of TMZ on GCSCs proliferation (being less effective on PCSCs) by decreasing MGMT expression, promoting HDAC4 nuclear translocation and activating apoptotic pathway.ConclusionsAlthough further studies are needed to determine the exact mechanism by which LEV makes GBM stem cells more sensitive to TMZ, these results suggest that the clinical therapeutic efficacy of TMZ in GBM might be enhanced by the combined treatment with LEV.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0626-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis

et al. 2018

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“…Accordingly, patients are typically weaned off the drug as soon as clinically possible [ 45 ]. Despite reports citing corticosteroid-mediated regression of GBM [ 51 , 52 ], it is widely held that corticosteroid use, particularly concomitant with radiation and chemotherapy, compromises survival of glioblastoma patients [ 43 , 44 ]. Moreover, its effect on global immunosuppression [ 53 ] has further contributed to the general perception that high dose, long-term use of Dex may not provide sufficient treatment benefit to GBM patients apart from its role as palliative therapy.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo

Nair

Romero

Mahtabfar

et al. 2018

IJMS

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Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor–related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. It does so by triggering α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV). How Dex specifically activates α5 integrin in these GBM lines is unknown. Several chaperone proteins are known to activate integrins, including calreticulin (CALR). We explore the role of CALR as a potential mediator of Dex-dependent induction of α5 integrin activity in primary human GBM cells. We use CALR knock-down and knock-in strategies to explore the effects on FNMA, aggregate compaction, and dispersal velocity in vitro, as well as dispersal ex vivo on extirpated mouse retina and brain slices. We show that Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated FNMA. Overexpression of CALR in GBM cells activates FNMA, increases compaction, and decreases DV in vitro and on explants of mouse retina and brain slices. Our results define a novel interaction between Dex, CALR, and FNMA as inhibitors of GBM dispersal.

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“…There has been no report of the expression of SV2A in ACC. With regard to the anti-tumor activity of levetiracetam, a case of glioblastoma multiforme (which did not include an examination of SV2A) that regressed with levetiracetam and dexamethasone was reported ( 13 ). Our present patient showed continuous regression of the tumor while on levetiracetam without any systemic cancer-targeted therapy, corticosteroids or folk/home remedies, suggesting that the response was due to the levetiracetam.…”

Section: Discussionmentioning

confidence: 99%

A Favorable Response to Levetiracetam in a Patient with Metastatic Adenoid Cystic Carcinoma

et al. 2018

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Adenoid cystic carcinoma (ACC) is a rare cancer, and there are no standard-of-care treatments for patients with metastatic ACC. We herein report a patient with lung metastasis of ACC who achieved a favorable response to levetiracetam. A 52-year-old Japanese man was admitted to our hospital because of multiple lung metastases of ACC. We performed first-line chemotherapy with cisplatin plus gemcitabine, and subsequently oral S-1 as second-line chemotherapy, which resulted in disease progression. The patient developed symptomatic epilepsy and received levetiracetam (250 mg twice daily). At five months after the initiation of levetiracetam, chest computed tomography showed regression of the metastatic lung lesions.

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Regression of a glioblastoma multiforme: spontaneous versus a potential antineoplastic effect of dexamethasone and levetiracetam

Cited by 11 publications

References 23 publications

Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis

Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis

Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo

A Favorable Response to Levetiracetam in a Patient with Metastatic Adenoid Cystic Carcinoma

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