Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model

Abstract

Glioblastoma multiforme is one of the most common and aggressive primary brain tumors in adults. High glutamate levels are thought to contribute to glioma growth. While research has focused on understanding glutamate signaling in glioma cells, little is known about the role of glutamate between glioma and astrocyte interactions. To study the relationship between astrocytes and tumor cells, the CNS-1 rodent glioma cell line was used. We hypothesized increased glutamate uptake by astrocytes would negatively affect CNS-1 cell growth. Primary rodent astrocytes and CNS-1 cells were co-cultured for 7 days in a Boyden chamber in the presence of 5 mM glutamate. Cells were treated with propentofylline, an atypical synthetic methylxanthine known to increase glutamate transporter expression in astrocytes. Our results indicate astrocytes can increase glutamate uptake through the GLT-1 transporter, leading to less glutamate available for CNS-1 cells, ultimately resulting in increased CNS-1 cell apoptosis. These data suggest that astrocytes in the tumor microenvironment can be targeted by the drug, propentofylline.

HIV-1, methamphetamine and astrocytes at neuroinflammatory Crossroads

“…PPF has also been shown to impair reinstatement of cocaine seeking behavior, which was dependent upon GLT-1/EAAT-2 expression and function (Reissner et al, 2014 ). PPF therapy increases EAAT-2 expression in astrocytes and dampens pro-inflammatory cytokine levels (Tawfik et al, 2006 ; Sweitzer and De Leo, 2011 ; Jacobs and De Leo, 2013 ). Since dysregulation of astrocyte EAAT-2 expression and function is implicated in both HAND and METH abuse, PPF could potentially target astrogliosis-mediated excitotoxicity and propagation of the neuroinflammatory environment by glia.…”

Glutamate transporters in the biology of malignant gliomas

“…Currently prescribed drugs such as valproic acid [168,169] and beta-lactam antibiotics [170] increase EAAT expression and may prove to be beneficial in regulating peritumoral glutamate levels and decreasing tumor growth. Propentofylline, a drug which increases EAAT1 and EAAT2 expression, increases astrocytic glutamate uptake in vitro , and causes increased glioma cell apoptosis as a result of decreased extracellular glutamate concentration [171]. These an other in vitro studies suggest pharmacologically increasing EAAT expression in the tumor or in peritumoral tissues may be neuroprotective and an effective adjuvant therapy to decrease tumor growth [172,12,173,174,116].…”

Role of glia in neuropathic pain

“…Reduction in the expression and uptake activity of glutamate transporters plays an essential role in both the induction and persistence of pain following peripheral nerve injury and in taxol-induced hyperalgesia (94,95). Glutamate transporter expression is consistently downregulated in spinal models of pathological pain; conversely, their increased expression or function can prevent pain from developing (96,97). For example, the drug propentofylline has protective effects against postischemic damage in the CNS by potent dose-dependent induction of glutamate transporter-1 mRNA and protein expression, accompanied by inhibition of CCL2 release.…”

“…For example, the drug propentofylline has protective effects against postischemic damage in the CNS by potent dose-dependent induction of glutamate transporter-1 mRNA and protein expression, accompanied by inhibition of CCL2 release. Conversely, injection of the glutamate uptake blocker threo-beta-benzyloxyaspartate leads to the manifestation of spontaneous nociceptive behavior (96,97).…”