Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma.
OBJECTIVE
Glutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo.


METHODS
Three GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells.


RESULTS
Riluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05).


CONCLUSIONS
Riluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.
['Yamada|Tetsuya|T|', 'Tsuji|Shohei|S|', 'Nakamura|Shinsuke|S|', 'Egashira|Yusuke|Y|', 'Shimazawa|Masamitsu|M|', 'Nakayama|Noriyuki|N|', 'Yano|Hirohito|H|', 'Iwama|Toru|T|', 'Hara|Hideaki|H|']
D000818:Animals D018906:Antineoplastic Agents, Alkylating D000971:Antineoplastic Combined Chemotherapy Protocols D001932:Brain Neoplasms D045744:Cell Line, Tumor D049109:Cell Proliferation D015254:DNA Modification Methylases D004260:DNA Repair D045643:DNA Repair Enzymes D004357:Drug Synergism D018691:Excitatory Amino Acid Antagonists D015972:Gene Expression Regulation, Neoplastic D005909:Glioblastoma D006801:Humans D051379:Mice D008810:Mice, Inbred C57BL D019782:Riluzole D000077204:Temozolomide D025521:Tumor Suppressor Proteins D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
riluzole temozolomide MGMT glioblastoma combinatorial therapy oncology