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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01104

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

 Alexandra Y. Tsidulko1, Cynthia Bezier2, 3, Gabin de La Bourdonnaye3, 4,  Anastasia Suhovskih1, 3,  Tatiana Pankova1, Galina Kazanskaya1, 5,  Svetlana Aidagulova6 and  Elvira V. Grigorieva1, 3*
  • 1Institute of Molecular Biology and Biophysics (RAS), Russia
  • 2Université Sorbonne Paris Cité, France
  • 3Novosibirsk State University, Russia
  • 4Institut National des Sciences Appliquées de Toulouse, France
  • 5Novosibirsk Scientific Research Institute of Pathology, Russia
  • 6Novosibirsk State Medical University, Russia

Temozolomide is a conventional chemotherapy drug for adjuvant treatment of glioblastoma multiforme (GBM), often accompanied by dexametasone to prevent brain edema 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 the 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. Dexamethasone (DXM) treatment affected both PG core proteins expression (mainly syndecan-1, glypican-1, decorin, biglycan, lumican, versican, brevican, NG2) and heparan sulfate (HS) and chondroitin sulfate (CS) content in organotypic brain slice culture ex vivo and experimental animals in vivo in a dose-dependent manner. Temozolomide (TMZ) treatment did not result in 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 of 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 affect proteoglycan structure and composition in normal brain tissue, being a negative factor involved in brain ECM deterioration and formation of the favorable 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 temozolomide.

Keywords: Gliobastoma multiforme, Temozolamide, Dexameathasone, Extracellar matrix, proteoglycan, Heparan sulfate, chondroitin sulfate

Received: 13 Jun 2018; Accepted: 10 Sep 2018.

Edited by:

Ahmed Lasfar, Rutgers University, The State University of New Jersey, United States

Reviewed by:

Shiv K. Gupta, Mayo Clinic, United States
Sujuan Guo, Dana–Farber Cancer Institute, United States  

Copyright: © 2018 Tsidulko, Bezier, de La Bourdonnaye, Suhovskih, Pankova, Kazanskaya, Aidagulova and Grigorieva. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Elvira V. Grigorieva, Institute of Molecular Biology and Biophysics (RAS), Novosibirsk, 630117, Russia, elv_grig@yahoo.com