Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma

Yamada, Tetsuya; Tsuji, Shohei; Nakamura, Shinsuke; Egashira, Yasuyuki; Shimazawa, Masamitsu; Nakayama, Noriyuki; Yano, Hirohito; Iwama, Toru; Hara, Hideaki

doi:10.3171/2019.12.jns192682

Cited by 19 publications

(16 citation statements)

References 38 publications

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“… Channel Tumour Drug References Cav3.2 GSC Mibefradil [ 92 ] Cav1.1, Cav1.2, Cav1.3, Cav1.4 Rat Derived GBM GBM mouse models GBM cell lines Pimozide Fluspirilene [ 107 , 108 , 109 ] Nav1.1 and Nav1.2. Human GBM Valporate Levetiracetam [ 110 , 111 , 112 ] Nav1.4 and Nav1.5 GBM cell line Riluzole [ 113 , 114 ] Kv1.4 GBM cell line Tamoxifen [ 115 ] Kv1.3 Human and mouse GBM biopsies Clofazimine [ 116 , 117 ] EAG1 Glioma Imipramine [ 118 , 119 ] …”

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

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Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

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Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

“…A synergistic effect of TMZ and riluzole was seen in MGMT positive cell lines, however synergy was not observed in MGMT negative lines. Significant dose and time dependant inhibition of GBM cell growth was clear [ 114 ].…”

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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“…Therefore, new treatments that can prevent or overcome resistance mechanisms in GBM are needed. So far, no significant efficacy with therapeutic agents alone has been demonstrated (Yamada et al, 2020). Our study intended to investigate the effect of LAU-0901, ELV-N34:6, Avastin and their combination that would significantly increase the probability of survival of mice with intracranial implantation of the luciferase-modified U87MG tumor cells as potential treatments for GBM.…”

Section: Discussionmentioning

confidence: 99%

Combined Therapy With Avastin, a PAF Receptor Antagonist and a Lipid Mediator Inhibited Glioblastoma Tumor Growth

et al. 2021

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Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.

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“…In addition, riluzole was also able to downregulate MGMT expression induced by TMZ. TMZ combined with riluzole could significantly reduce the average maximum cross-sectional area and volume of the tumors in mice injected with GL261 cells, suggesting TMZ + riluzole as a potential treatment ( 77 ). The expression level of MGMT is associated with the efficacy of treatment.…”

Section: Temozolomidementioning

confidence: 99%

Research progress of anti-glioma chemotherapeutic drugs (Review)

et al. 2022

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Glioma is the most common primary intracranial malignancy in the central nervous system. At present, the most important treatment option is surgical resection of the tumor combined with radiotherapy and chemotherapy. The principle of operation is to remove the tumor to the maximal extent on the basis of preserving brain function. However, prominent invasive and infiltrative proliferation of glioma tumor cells into the surrounding normal tissues frequently reduces the efficacy of treatment. This in turn worsens the prognosis, because the tumor cannot be completely removed, which can readily relapse. Chemotherapeutic agents when applied individually have demonstrated limited efficacy for the treatment of glioma. However, multiple different chemotherapeutic agents can be used in combination with other treatment modalities to improve the efficacy while circumventing systemic toxicity and drug resistance. Therefore, it is pivotal to unravel the inhibitory mechanism mediated by the different chemotherapeutic drugs on glioma cells in preclinical studies. The aim of the present review is to provide a summary for understanding the effects of different chemotherapeutic drugs in glioma, in addition to providing a reference for the preclinical research into novel chemotherapeutic agents for future clinical application.

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Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma

Cited by 19 publications

References 38 publications

Ion Channels as Therapeutic Targets in High Grade Gliomas

Ion Channels as Therapeutic Targets in High Grade Gliomas

Combined Therapy With Avastin, a PAF Receptor Antagonist and a Lipid Mediator Inhibited Glioblastoma Tumor Growth

Research progress of anti-glioma chemotherapeutic drugs (Review)

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