Tamoxifen-resistant glioma-cell sub-populations are characterized by increased migration and proliferation.
Multifocal tumor recurrence of glioblastomas occurs in up to 14% of patients. In a parallel phase-II-study investigating post-operative treatment with tamoxifen (TAM), carboplatin and radiation therapy for glioblastomas, 16 of 49 patients (33%) showed multifocal recurrence, which developed after a mean of 46 weeks, raising the question of an association with therapy. We studied the interrelation of proliferation and migration in the presence of different protein-kinase-C(PKC) inhibitors (TAM, staurosporine, hypericin) in 2 glioma cell lines. In addition, 3 cell lines were selected for TAM resistance by repeated cycles of treatment with sub-lethal concentrations of TAM. The proliferative capacity and the invasive potential of selected sub-populations were assessed using growth-curve experiments, monolayer migration, and cell-adhesion assays. Treatment with all PKC inhibitors tested resulted in a dose-dependent decrease of proliferation, while motility was altered only at significantly higher doses. Resistance to TAM occurred in all 3 selected cell lines. The TAM-resistant sub-populations showed significantly increased proliferation, migration and adhesion as compared with the parental (non-selected) cell line. The higher incidence of multifocal disease after TAM treatment was paralleled by increased migratory potential of TAM-treated cells in vitro.
Puchner
M J
MJ
Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany. puchner@plexus.uke.uni-hamburg.de
Giese
A
A
D000873:Anthracenes; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D010569:Perylene; C004965:hypericin; D011493:Protein Kinase C; D019311:Staurosporine