1. Overexpression of TIMP-1 and Sensitivity to Topoisomerase Inhibitors in Glioblastoma Cell Lines
- Author
-
Charlotte Aaberg-Jessen, Nils Brünner, Louise Fogh, Bjarne Winther Kristensen, Bo Halle, and Mia D. Sørensen
- Subjects
0301 basic medicine ,Cancer Research ,Bevacizumab ,Topoisomerase Inhibitors ,medicine.drug_class ,medicine.medical_treatment ,Apoptosis ,Gene Expression Regulation, Enzymologic ,Pathology and Forensic Medicine ,03 medical and health sciences ,chemistry.chemical_compound ,Organ Culture Techniques ,TIMP-1 ,0302 clinical medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Rats, Wistar ,Chemosensitivity ,Cell Proliferation ,Chemotherapy ,Tissue Inhibitor of Metalloproteinase-1 ,biology ,Brain Neoplasms ,Topoisomerase ,General Medicine ,Transfection ,Molecular biology ,Rats ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor ,Irinotecan ,030104 developmental biology ,Animals, Newborn ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,TOP inhibitors ,030220 oncology & carcinogenesis ,biology.protein ,Antibody ,Glioblastoma ,Topoisomerase inhibitor ,medicine.drug - Abstract
The multifunctional protein - tissue inhibitor of metalloproteinases-1 (TIMP-1) - has been associated with a poor prognosis in several types of cancers including glioblastomas. In addition, TIMP-1 has been associated with decreased response to chemotherapy, and especially the efficacy of the family of topoisomerase (TOP) inhibitors has been related to TIMP-1. As a second line treatment of glioblastomas, the vascular endothelial growth factor (VEGF) antibody bevacizumab is administered in combination with the TOP1 inhibitor irinotecan and glioblastoma cell levels of TIMP-1 could therefore potentially influence the efficacy of such treatment. In the present study, we aimed to investigate whether a high TIMP-1 expression in glioblastoma cell lines would affect the sensitivity to TOP inhibitors, and whether TIMP-1 overexpressing cells would have alterered growth and invasion. We established TIMP-1 overexpressing subclones from two human glioblastoma cell lines. TIMP-1 overexpressing U87MG cells were significantly more resistant than low TIMP-1 expressing clones and parental cells when exposed to SN-38 (TOP1 inhibitor) or epirubicin (TOP2 inhibitor). No significant differences were observed for the TIMP-1 transfected A172 cells. Implantation of both U87MG and A172 spheroids into organotypic brain slice cultures revealed a reduced growth of TIMP-1 overexpressing U87MG spheroids, however, no significant differences in invasion were observed. The present study suggests that TIMP-1 overexpression reduces the effect of TOP inhibitors in glioblastoma. TIMP-1 also appeared to reduce spheroid growth, but did not influence invasion. Whether TIMP-1 plays a role in irinotecan resistance and has a predictive potential in glioblastoma patients remains to be elucidated.
- Published
- 2017