Temozolomide (TMZ) is a main drug for chemotherapy of glioblastoma multiforme (GBM). During the treatment, both GBM tumour and surrounding normal brain are exposed to the drug, and its effects on the normal brain tissue are not investigated. Survival and invasion of GBM cells depend not only on their characteristics but also on the structure of extracellular matrix (ECM) of brain tissue, which consists mainly of glycosylated molecules such as proteoglycans (PGs) and glycosaminoglycans (GAGs). Here, we aimed to investigate the effects of TMZ on PGs and GAGs expression in normal brain tissue.
Two-month-old Wistar rats were used in the study, and effects of TMZ treatment on PGs (syndecan-1, glypican-1, perlecan, decorin, biglycan, lumican, brevican, neurocan, CSPG4/NG2, aggrecan) were studied using real-time RT-PCR and IHC analyses.
Treatment with TMZ had almost no effects on the overall transcriptional activity of the PGs core proteins in normal brain tissue but resulted in a 2-fold increase of GAGs content (both heparin sulfates and chondroitin sulfates). Different TMZ-based drugs demonstrated different effects on the PGs core proteins expression - treatment with some of them resulted in significant decrease in syndecan-1, glypican-1, perlecan and lumican expression. Moreover, treatment with combination of TMZ and dexamethasone, commonly used to treat glioma-induced edema, led to the most dramatic changes in PGs composition in the brain tissue at both core protein and GAG levels.
The obtained results demonstrate that chemotherapy with temozolomide affects proteoglycan composition and ECM structure in normal brain tissue. These changes might be involved in the formation of the tumourigenic niche for the expansion of the residual glioma cells and the disease progression.
Clinical trial identification
Legal entity responsible for the study
Federal Research Center of Fundamental and Translational Medicine.
Russian Science Foundation (RSF grant 16-15-10243). Tsidulko A. was funded by individual scholarship of Russian Federation President for young scientists (SP-5435.2018.4).
All authors have declared no conflicts of interest.