gms | German Medical Science

70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12.05. - 15.05.2019, Würzburg

The role of the calpain/calpastatin system in chemoresistance of glioblastoma

Die Rolle des Calpain/Calpastatin Systems bei der Chemotherapie-Resistenz von Glioblastomen

Meeting Abstract

  • Ricarda Hannen - Philipps-Universität Marburg, Klinik für Neurochirurgie, Marburg, Deutschland
  • Chia-yi Chen - Universität Freiburg, Pathologie, Freiburg, Deutschland
  • Oliver Schilling - Universität Freiburg, Pathologie, Freiburg, Deutschland
  • Jörg-Walter Bartsch - Philipps-Universität Marburg, Klinik für Neurochirurgie, Marburg, Deutschland
  • Christopher Nimsky - Philipps-Universität Marburg, Klinik für Neurochirurgie, Marburg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie. Würzburg, 12.-15.05.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocP071

doi: 10.3205/19dgnc409, urn:nbn:de:0183-19dgnc4096

Published: May 8, 2019

© 2019 Hannen et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: Infiltration of tumor cells into the surrounding brain tissue and development of resistance mechanisms towards adjuvant radio- and chemotherapy are two main aspects that need to be addressed in order to establish an effective treatment for Glioblastoma (GBM). In both processes, calcium-dependent proteases (calpains) could be involved. Calpains are cysteine proteases, naturally inhibited by calpastatins, and highly expressed in tumor cells. This study aims to target the calpain/calpastatin system for therapeutic purposes in GBM.

Methods: Expression analysis was performed on primary tissue from GBM and gliomas grade II and III (n=20 each) using qPCR. Furthermore the expression profiles between first manifested and patient-matched recurrent GBM (n=20 patients) was compared and correlated to patient outcome. The role of calpains in several GBM cell lines and in patient derived primary GBM cells was investigated and the activity of calpains was determined by fluorescence analysis in correlation to expression levels of calpastatin. To inhibit calpains, cells were treated with 50 µM PD 150606, a specific calpain inhibitor, either alone or in combination with Temozolomide (TMZ).

Results: Calpains 1 and 2 were up to six-fold up-regulated in GBM compared to gliomas grade II and III. In addition to a correlation between calpain expression and malignancy, it was shown that calpains are over-expressed in recurrent GBM tissue compared to patient matched first manifested GBM tissue (11/19 for Calpain 1; 16/19 for Calpain 2). The observed trend was further investigated in order to discover the role of calpains especially in manifestation of recurrent GBMs. Calpain activities were determined in GBM cell lines and in patient derived GBM cells and were inhibited by treatment with 50 µM PD 150606. In most cell lines, an additive effect of co-treatment with PD150606/TMZ was observed. Only those cells were sensitized to TMZ treatment that exerted cellular calpain activity, suggesting that calpain activity is part of the intrinsic TMZ resistance of GBM cells. Sensitization of calpain inhibitor treated cells to TMZ was concomitant with enhanced apoptosis, as revealed by increased Caspase-3 activity in responding GBM cells.

Conclusion: Here we show that inhibition of calpains facilitates TMZ induced apoptosis of GBM cells, suggesting that a co-treatment with TMZ and calpain inhibitor in GBMs could provide a better outcome than the standard TMZ chemotherapy.