Abstract
Glioblastomas (GBMs) are tumors that have a high ability to migrate, invade and proliferate in the healthy tissue, what greatly impairs their treatment. These characteristics are associated with the complex microenvironment, formed by the perivascular niche, which is also composed of several stromal cells including astrocytes, microglia, fibroblasts, pericytes and endothelial cells, supporting tumor progression. Further microglia and macrophages associated with GBMs infiltrate the tumor. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by GBM cells and exploited in the process. In this review we discuss the context of the GBM microenvironment together with the actions of flavonoids, which have attracted scientific attention due to their pharmacological properties as possible anti-tumor agents. Flavonoids act on a variety of signaling pathways, counteracting the invasion process. Luteolin and rutin inhibit NFκB activation, reducing IL-6 production. Fisetin promotes tumor apoptosis, while inhibiting ADAM expression, reducing invasion. Naringenin reduces tumor invasion by down-regulating metalloproteinases expression. Apigenin and rutin induce apoptosis in C6 cells increasing TNFα, while decreasing IL-10 production, denoting a shift from the immunosuppressive Th2 to the Th1 profile. Overall, flavonoids should be further exploited for glioma therapy.
Highlights
Glioblastomas (GBMs) are high-grade malignant brain tumors classified as grade IV by the World Health Organization (WHO)
Flavonoids are a group of phenolic secondary metabolites present in several types of plants; They consist of a three-ring structure: two benzene rings (A and B rings) interconnected by a heterocyclic ring (C-ring) (Figure 3) [82]
They found that the effects depended on inhibiting phosphorylation and activating Akt signaling pathway, inducing the expression of apoptosis-related proteins such as cleaved caspase-3, cytochrome c, poly ADP ribose polymerase (PARP) and p53, in addition to promoting Forkhead Box O3A (FOXO3) to be transported from the cytosol to the nucleus leading to the transition of p21 and p27 proteins
Summary
Glioblastomas (GBMs) are high-grade malignant brain tumors classified as grade IV by the World Health Organization (WHO). Studies conducted over the last two decades, and especially in the last years, have demonstrated the antitumor potential of the flavonoids both in in vitro and in in vivo models of GBMs [5,6,7,8]. These compounds showed the potential to modulate the inflammatory response of microglia/macrophages associated with tumorigenesis inhibition [9,10,11]. Further flavonoidpromoted anti-inflammatory effects on CNS-resident and invading immune cells are discussed as a new concept for GBM-adjuvant treatment based on immunomodulation
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