Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition.

ABSTRACT: Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200?kHz, 1.7?V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4?µM). Cells were counted after 24, 48, and 72?h of treatment and at 24 and 72?h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72?h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72?h compared to either treatment alone (-78.6% vs. TTFields, P?=?0.0337; -52.6% vs. IN-3, P?=?0.0205), and reduced the number of viable cells (62% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P?P?=?0.0002; IN-3 4%, P?P?=?0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.

SUBMITTER: Kessler AF 

PROVIDER: S-EPMC6125382 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature