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 < 0.0001). The apoptotic rate increased to 44% (TTFields 14%, P = 0.0002; IN-3 4%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92% at 72 h EOT if IN-3 treatment was continued (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.
Highlights
Malignant gliomas are the most prevalent, highly aggressive, invasive, and difficult to treat primary brain tumors in adults
TTFields are a new therapy approved by the FDA for newly diagnosed and recurrent glioblastoma multiforme (GBM) and are considered a fourth treatment modality that improves overall survival with a minimal impact on patients QoL6–8
An optimal frequency of 200 kHz has been established for the treatment of GBM, which is in accordance with previously published[11,12,18] as well as our own data derived from cell culture experiments that show that GaMG cells are more sensitive to TTFields than U87-MG cells
Summary
Malignant gliomas are the most prevalent, highly aggressive, invasive, and difficult to treat primary brain tumors in adults. In spite of this multimodal approach the prognosis is unfavorable with a median overall survival (OS) of around 16 months, a progression-free survival of 6.9 months and a 5-year survival of only 9.8%4,5. Tumor treating fields (TTFields) at 200 kHz are a novel approved GBM treatment modality that demonstrated an improved median OS by 4.9 months in newly diagnosed GBM patients with only minor side effects in a clinical phase III trial[6] and no deterioration in QoL7,8. These alternating electric fields have a frequency range of 100–300 kHz and a field intensity of 1–3 V/cm.
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