Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models

Abstract

Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. Conclusions Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo

“…In contrast to our report, they demonstrated mediation of riluzole’s effects through AKT-mTOR signaling, whereas our findings implicate MAPK signaling. In a significant corroboration of our report, Yohay et al demonstrated that riluzole delivered either locally (loaded on a polymer) or systemically had significant anti-glioma effects, and strikingly the effect of the of systemic administration synergized strongly with radiotherapy [30]. Others, too, have demonstrated the activity of riluzole or LY341495 on proliferation, survival, and/or migration of glioma cells [31, 32].…”

Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin

“…a beneficial anticancer effect, on both human colorectal cancer cell lines T84 and HT29 after riluzole treatment. Interestingly, this effect of riluzole treatment has been observed for several other cancer cell types (Yamamoto et al, 2017) including melanoma, glioma and prostate (Akamatsu et al, 2009;Le et al, 2010;Yohay et al, 2014). More important, riluzole had no negative effects on the chemotherapeutic action of oxaliplatin.…”

Glutamate in cancers: from metabolism to signaling

“…Riluzole has shown promising anti-tumor effect in glioma, melanoma, breast and prostate cancers, and osteosarcoma as well [ 72 , 80 – 81 , 101 ] . Combination of riluzole with the other glutamate antagonistic drugs, such as memantine or valproate, is reported to have better effects for glioma treatment [ 101 – 102 ] .…”