Effect of duty cycles of tumor‑treating fields on glioblastoma cells and normal brain organoids

Abstract

Tumor-treating fields (TTFields) are emerging cancer therapies based on alternating low-intensity electric fields that interfere with dividing cells and induce cancer cell apoptosis. However, to date, there is limited knowledge of their effects on normal cells, as well as the effects of different duty cycles on outcomes. The present study evaluated the effects of TTFields with different duty cycles on glioma spheroid cells and normal brain organoids. A customized TTFields system was developed to perform in vitro experiments with varying duty cycles. Three duty cycles were applied to three types of glioma spheroid cells and brain organoids. The efficacy and safety of the TTFields were evaluated by analyzing the cell cycle of glioma cells, and markers of neural stem cells (NSCs) and astrocytes in brain organoids. The application of the TTFields at the 75 and 100% duty cycle markedly inhibited the proliferation of the U87 and U373 compared with the control. FACS analysis revealed that the higher the duty cycle of the applied fields, the greater the increase in apoptosis detected. Exposure to a higher duty cycle resulted in a greater decrease in NSC markers and a greater increase in glial fibrillary acidic protein expression in normal brain organoids. These results suggest that TTFields at the 75 and 100% duty cycle induced cancer cell death, and that the neurotoxicity of the TTFields at 75% was less prominent than that at 100%. Although clinical studies with endpoints related to safety and efficacy need to be performed before this strategy may be adopted clinically, the findings of the present study provide meaningful evidence for the further advancement of TTFields in the treatment of various types of cancer.

Real-Time Monitoring of the Effect of Tumour-Treating Fields on Cell Division Using Live-Cell Imaging

“…Although there have been many successful clinical trials with TTFields, and their in vivo safety has been established in several studies [ 21 , 54 ], there are limited data available on the effects of TTFields on normal cells. In the recent work of Ye et al, it was found that TTFields applied to normal brain organoids in vitro induced cell damage that could lead to apoptosis [ 69 ]. In combination with our results, these findings strongly imply that treatment with TTFields should be accurately directed at tumour sites and applied such that the exposure of healthy tissues is minimized.…”

Development of glioblastoma organoids and their applications in personalized therapy

“…Biopeptide-based therapeutics must use advanced GBM in vitro models, such as organoids, to explore combination approaches for clinically including bioactive peptides to standard cancer treatments 73 . Brain organoids have also been reported to be applied to the latest electric field therapy, and have shown good auxiliary value in evaluation of the efficacy and safety of electric field therapy 74 . The research applications of GBOs are detailed in Table 2 .…”

Applications of organoid technology to brain tumors

“…For example, TTFields showed inhibitory effects on GBM cell proliferation at both 75% and 100% duty cycles; the neurotoxicity of brain organoids at 75% was less prominent than at 100%, indicating that 75% may be a better choice. 114 The targeted drug UM-002 employed in GLICO showed that higher concentrations (>500 nM)…”

“…Brain organoids as a “mini brain” can be used as a surrogate to evaluate the side effects of antitumor therapy and provide valuable information for clinical decisions. For example, TTFields showed inhibitory effects on GBM cell proliferation at both 75% and 100% duty cycles; the neurotoxicity of brain organoids at 75% was less prominent than at 100%, indicating that 75% may be a better choice 114 . The targeted drug UM‐002 employed in GLICO showed that higher concentrations (>500 nM) reduced GBM cell proliferation but also induced toxicity in normal brain organoids.…”