Conventional Anti-glioblastoma Chemotherapy Affects Proteoglycan Composition of Brain Extracellular Matrix in Rat Experimental Model in vivo

Abstract

Temozolomide (TMZ) is a conventional chemotherapy drug for adjuvant treatment of glioblastoma multiforme (GBM), often accompanied by dexamethasone (DXM) to prevent brain oedema and alleviate clinical side effects. Here, we aimed to investigate an ability of the drugs to affect normal brain tissue in terms of proteoglycan (PG) composition/content in experimental rat model in vivo. Age- and brain zone-specific transcriptional patterns of PGs were demonstrated for 8, 60, and 120 days old rats, and syndecan-1, glypican-1, decorin, biglycan, and lumican were identified as the most expressed PGs. DXM treatment affected both PG core proteins expression (mainly syndecan-1, glypican-1, decorin, biglycan, lumican, versican, brevican, and NG2) and heparan sulphate (HS)/chondroitin sulphate (CS) content in organotypic brain slice culture ex vivo and experimental animals in vivo in a dose-dependent manner. TMZ treatment did not result in the significant changes in PG core proteins expression both in normal rat brain hippocampus and cortex in vivo (although generics did), but demonstrated significant effects onto polysaccharide HS/CS content in the brain tissue. The effects were age- and brain zone-specific and similar with the age-related PGs expression changes in rat brain. Combination of TMZ with DXM resulted in the most profound deterioration in PGs composition and content in the brain tissue both at core protein and glycosaminoglycan levels. Taken together, the obtained results demonstrate that conventional anti-glioblastoma therapy affects proteoglycan structure and composition in normal brain tissue, potentially resulting in deterioration of brain extracellular matrix and formation of the favourable tumorigenic niche for the expansion of the residual glioma cells. During the TMZ chemotherapy, dose and regimen of DXM treatment matter, and repetitive low DXM doses seem to be more sparing treatment compared with high DXM dose(s), which should be avoided where possible, especially in combination with TMZ.

Long-Term Exposure to Temozolomide Affects Locomotor Activity and Cartilage Structure of Elderly Experimental Rats

“…We have shown for the first time that the long-term administration of TMZ to elderly Wistar rats leads to an increase in the total content of GAGs and the redistribution of sulfated GAGs between chondrocytes and the matrix of the epiphyseal cartilage of the knee joints. It is interesting that similar changes in GAGs content were observed in the rat brain tissue, where TMZ increases the CS content (one of the main classes of GAGs) in the cerebral cortex of rats after 5 days of drug administration [37].…”

Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

“…144 TMZ treatment also alters proteoglycan and GAG composition, with the combination of TMZ and dexamethasone resulting in deterioration of proteoglycan and GAG content. 145 Other agents promote TME remodelling that slows tumour progression. Microtubule inhibitors target cell division, but they can also reduce the invasive capacity of tumour cells by reducing MMP-2 expression.…”

Proteoglycans as Therapeutic Targets in Brain Cancer

“…Tsidulko's work demonstrated that PG composition and ECM structure in normal brain tissue were affected during temozolomide induced chemotherapy. These changes were believed to participate in the development of the tumorigenic niche for the expansion of the residual glioma cells and the disease progression (59). Recently, researchers have reviewed the influences of KS sulfation on electrosensory tissues and neuronal regulation.…”