Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.

Keywords: GBM; cerebral oedema; dexamethasone; glioblastoma multiforme therapy; pharmacogenomics.

Figure 1

Tumor-related oedema. Brain capillary endothelial cells (BCECs) are connected via tight junction (TJ) protein complexes that fuse endothelial cells together. When a brain tumor develops, particularly high-grade gliomas, TJs become permeable due to release of angiogenic factors and changes in protein component. These events cause blood brain barrier (BBB) breakdown and vasogenic oedema.

Figure 2

DEX mechanisms reducing tumor-induced brain oedema. DEX acting on both endothelial and tumor cells modulates the transcription of several gene products that control the BBB permeability.