TY - JOUR

T1 - Conventional anti-glioblastoma chemotherapy affects proteoglycan composition of brain extracellular matrix in rat experimental model in vivo

AU - Tsidulko, Alexandra Y.

AU - Bezier, Cynthia

AU - De La Bourdonnaye, Gabin

AU - Suhovskih, Anastasia V.

AU - Pankova, Tatiana M.

AU - Kazanskaya, Galina M.

AU - Aidagulova, Svetlana V.

AU - Grigorieva, Elvira V.

N1 - Publisher Copyright: © 2007 - 2018 Frontiers Media S.A. All Rights Reserved.

PY - 2018/10/2

Y1 - 2018/10/2

N2 - 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.

AB - 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.

KW - Chondroitin sulphate

KW - Dexamethasone

KW - Extracellular matrix

KW - Glioblastoma multiforme

KW - Glycosaminoglycan

KW - Heparan sulphate

KW - Proteoglycan

KW - Temozolomide

KW - temozolomide

KW - glioblastoma multiforme

KW - DEXAMETHASONE

KW - GLUCOCORTICOIDS

KW - TUMORS

KW - GLIOMA INVASION

KW - UP-REGULATION

KW - glycosaminoglycan

KW - dexamethasone

KW - CELLS

KW - CHONDROITIN SULFATE

KW - TEMOZOLOMIDE

KW - proteoglycan

KW - chondroitin sulphate

KW - SLICE CULTURES

KW - heparan sulphate

KW - extracellular matrix

KW - MOLECULAR-MECHANISMS

UR - http://www.scopus.com/inward/record.url?scp=85055335244&partnerID=8YFLogxK

U2 - 10.3389/fphar.2018.01104

DO - 10.3389/fphar.2018.01104

M3 - Article

C2 - 30333749

AN - SCOPUS:85055335244

VL - 9

SP - 1104

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

IS - OCT

M1 - 1104

ER -