Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer, with a median survival of less than 2 years after diagnosis. The tumor microenvironment plays a critical role in tumor invasion and progression. Microglia and infiltrating macrophages are the most abundant immune cells in the tumor. In the present study, we demonstrate that systemic propentofylline (PPF), an atypical methylxanthine with central nervous system (CNS) glial modulating and anti-inflammatory actions, significantly decreased tumor growth in a CNS-1 rat model of GBM by targeting microglia and not tumor cells. Rats received tumor injections of 1 × 10(5) CNS-1 cells in the right striatum with daily intraperitonial injections of PPF (50 mg/kg) or saline beginning the day of tumor injection. PPF did not cause apoptosis or decrease proliferation of CNS-1 tumor cells. Furthermore, we demonstrate, using in vitro methods, that PPF decreased microglial migration toward CNS-1 tumor cells and decreased MMP-9 expression. The effects of PPF were shown to be specific to microglia and not peripheral macrophages. These results support a differential functional role of resident microglia and infiltrating macrophages in the brain tumor environment. Our data highlight microglia as a crucial target for future therapeutic development and present PPF as a possible drug for treatment of human GBM.

Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies

“…Moreover, systemic administration of cyclosporine A (CsA) was shown to decrease glioma growth and angiogenesis by inhibiting microglia/macrophages infiltration by inducing cell death and blocking the expression and activity of important enzymes and cytokines required for tumor invasion [47]. Propentofylline (PPF), an atypical methylxanthine and glial modulating agent with anti-inflammatory actions, was also shown to be effective in reducing glioma growth by targeting microglia and possibly decreasing their expression of MMP-9 [48]. …”

Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway

“…Although the application of PPF in these various disorders has not yet been fully elucidated, the clinical trials revealed therapeutic efficacy, blood brain barrier permeability, and a minimal side effect profile [17]. It has been demonstrated that systemic PPF treatment decreased tumor growth in a CNS-1 rat model via modulation of microglia [18]. PPF inhibits the migration of microglia by decreasing TROY expression and suppresses the activation of downstream effector molecules, including Pyk2 and Rac1 [16].…”

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

“…We have previously demonstrated that PPF decreases tumor growth in the CNS-1 rat glioma model by decreasing microglial migration and expression of MMP-9 [15]. Here we present another mechanism of PPF’s action in astrocytes.…”

“…Our laboratory has previously shown that i.p. injection of PPF decreases tumor growth in a rodent glioma model by directly targeting the tumor microenvironment [15]. We demonstrated that PPF targets microglia; however, PPF is also known to have an effect on astrocytes in vivo and in vitro.…”