Effect of duty cycles of tumor‑treating fields on glioblastoma cells and normal brain organoids Corrigendum in /10.3892/ijo.2022.5397

Ye,Eunbi; Ye,Eunbi; Lee,Jung Eun; Lee,Jung Eun; Lim,Young-Soo; Lim,Young-Soo; Yang,Seung Ho; Yang,Seung Ho; Park,Sung-Min; Park,Sung-Min

doi:10.3892/ijo.2021.5298

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

Corrigendum in: /10.3892/ijo.2022.5397

Authors:
- Eunbi Ye
- Jung Eun Lee
- Young-Soo Lim
- Seung Ho Yang
- Sung-Min Park
View Affiliations

Affiliations: Department of Convergence IT Engineering, Pohang University of Science and Technology, Pohang‑si, Gyeongsangbuk‑do 37673, Republic of Korea, Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon‑si, Gyeonggi‑do 16247, Republic of Korea
Published online on: December 28, 2021 https://doi.org/10.3892/ijo.2021.5298
Article Number: 8
Copyright: © Ye et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R and Palti Y: Disruption of cancer cell replication by alternating electric fields. Cancer Res. 64:3288–3295. 2004. View Article : Google Scholar : PubMed/NCBI
2	Neuhaus E, Zirjacks L, Ganser K, Klumpp L, Schüler U, Zips D, Eckert F and Huber SM: Alternating electric fields (TTFields) activate Ca_v 1.2 channels in human glioblastoma cells. Cancers. 11:1102019. View Article : Google Scholar
3	Trusheim J, Dunbar E, Battiste J, Iwamoto F, Mohile N, Damek D, Bota DA and Connelly J: A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS Oncol. 6:29–43. 2017. View Article : Google Scholar
4	Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbalý V, et al: NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality. Eur J Cancer. 48:2192–2202. 2012. View Article : Google Scholar : PubMed/NCBI
5	Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, et al: Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA. 318:2306–2316. 2017. View Article : Google Scholar : PubMed/NCBI
6	Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, et al: Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA. 314:2535–2543. 2015. View Article : Google Scholar
7	Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, et al: Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci Rep. 5:180462015. View Article : Google Scholar : PubMed/NCBI
8	Hottinger AF, Pacheco P and Stupp R: Tumor treating fields: A novel treatment modality and its use in brain tumors. Neuro Oncol. 18:1338–1349. 2016. View Article : Google Scholar : PubMed/NCBI
9	Gera N, Yang A, Holtzman TS, Lee SX, Wong ET and Swanson KD: Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS One. 10:e01252692015. View Article : Google Scholar :
10	Kirson ED, Dbalý V, Tovaryš F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, et al: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 104:10152–10157. 2007. View Article : Google Scholar : PubMed/NCBI
11	Giladi M, Voloshin T, Shteingauz A, Munster M, Blat R, Porat Y, Schneiderman RS, Cahal S, Itzhaki A, Kirson E, et al: Alternating electric fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. J Immunol. 196(Suppl 1): 75.262016.
12	Silginer M, Weller M, Stupp R and Roth P: Biological activity of tumor treating fields in preclinical glioma models. Cell Death Dis. 8:e27532017. View Article : Google Scholar
13	Tuszynski JA, Wenger C, Friesen DE and Preto J: An overview of sub-cellular mechanisms involved in the action of TTFields. Int J Environ Res Public Health. 13:11282016. View Article : Google Scholar :
14	Wenger C, Miranda PC, Salvador R, Thielscher A, Bomzon Z, Giladi M, Mrugala MM and Korshoej AR: A review on tumor-treating fields (TTFields): Clinical implications inferred from computational modeling. IEEE Rev Biomed Eng. 11:195–207. 2018. View Article : Google Scholar : PubMed/NCBI
15	Pampaloni F, Reynaud EG and Stelzer EH: The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol. 8:839–845. 2007. View Article : Google Scholar : PubMed/NCBI
16	Vinci M, Gowan S, Boxall F, Patterson L, Zimmermann M, Lomas C, Mendiola M, Hardisson D and Eccles SA: Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol. 10:292012. View Article : Google Scholar : PubMed/NCBI
17	Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP and Knoblich JA: Cerebral organoids model human brain development and microcephaly. Nature. 501:373–379. 2013. View Article : Google Scholar : PubMed/NCBI
18	Di Lullo E and Kriegstein AR: The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 18:573–584. 2017. View Article : Google Scholar :
19	Kanner AA, Wong ET, Villano JL and Ram Z; EF-11 Investigators: Post-hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A™ system versus best physician's choice chemotherapy. Semin Oncol. 41(Suppl 6): S25–S34. 2014. View Article : Google Scholar
20	Benson L: Tumor treating fields technology: Alternating electric field therapy for the treatment of solid tumors. Semin Oncol Nurs. 34:137–150. 2018. View Article : Google Scholar : PubMed/NCBI
21	Lacouture ME, Davis ME, Elzinga G, Butowski N, Tran D, Villano JL, DiMeglio L, Davies AM and Wong ET: Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma. Semin Oncol. 41(Suppl 4): S1–S14. 2014. View Article : Google Scholar : PubMed/NCBI
22	Toms SA, Kim CY, Nicholas G and Ram Z: Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: A subgroup analysis of the EF-14 phase III trial. J Neurooncol. 141:467–473. 2019. View Article : Google Scholar :
23	Berkelmann L, Bader A, Meshksar S, Dierks A, Majernik GH, Krauss JK, Schwabe K, Manteuffel D and Ngezahayo A: Tumour-treating fields (TTFields): Investigations on the mechanism of action by electromagnetic exposure of cells in telophase/cytokinesis. Sci Rep. 9:76322019. View Article : Google Scholar
24	Plonsey R and Heppner DB: Considerations of quasistationarity in electrophysiological systems. Bull Math Biophys. 29:657–664. 1967. View Article : Google Scholar : PubMed/NCBI
25	Pennes HH: Analysis of tissue and arterial blood temperatures in the resting human forearm. J Appl Physiol (1985). 85:5–34. 1998. View Article : Google Scholar
26	Korshoej AR, Hansen FL, Thielscher A, von Oettingen GB and Sørensen JC: Impact of tumor position, conductivity distribution and tissue homogeneity on the distribution of tumor treating fields in a human brain: A computer modeling study. PLoS One. 12:e01792142017. View Article : Google Scholar : PubMed/NCBI
27	Yang SH, Hong YK, Jeun SS, Kim IS, Hong JT, Sung JH, Son BC, Lee SW, Kim MC and Lee KS: Assessment of cetuximab efficacy by bioluminescence monitoring of intracranial glioblastoma xenograft in mouse. J Neurooncol. 95:23–28. 2009. View Article : Google Scholar : PubMed/NCBI
28	Kim Y, Park N, Rim YA, Nam Y, Jung H, Lee K and Ju JH: Establishment of a complex skin structure via layered co-culture of keratinocytes and fibroblasts derived from induced pluripotent stem cells. Stem Cell Res Ther. 9:2172018. View Article : Google Scholar : PubMed/NCBI
29	Maxim Integrated Programmable Resolution 1-Wire Digital Thermometer. Maxim Integrated Products, Inc; San Jose, CA: 2019, https://datasheets.maximintegrated.com/en/ds/DS18B20.pdf.
30	Gatson NT, Barnholtz-Sloan J, Drappatz J, Henriksson R, Hottinger AF, Hinoul P, Kruchko C, Puduvalli VK, Tran DD, Wong ET, et al: Tumor treating fields for glioblastoma therapy during the COVID-19 pandemic. Front Oncol. 11:6797022021. View Article : Google Scholar : PubMed/NCBI
31	Mehta G, Hsiao AY, Ingram M, Luker GD and Takayama S: Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. J Control Release. 164:192–204. 2012. View Article : Google Scholar : PubMed/NCBI
32	Shi W, Blumenthal DT, Oberheim Bush NA, Kebir S, Lukas RV, Muragaki Y, Zhu JJ and Glas M: Global post-marketing safety surveillance of tumor treating fields (TTFields) in patients with high-grade glioma in clinical practice. J Neurooncol. 148:489–500. 2020. View Article : Google Scholar :
33	Lewis EM, Kaushik K, Sandoval LA, Antony I, Dietmann S and Kroll KL: Epigenetic regulation during human cortical development: Seqing answers from the brain to the organoid. Neurochem Int. 147:1050392021. View Article : Google Scholar
34	Aguilar AA, Ho MC, Chang E, Carlson KW, Natarajan A, Marciano T, Bomzon Z and Patel CB: Permeabilizing cell membranes with electric fields. Cancers (Basel). 13:22832021. View Article : Google Scholar
35	Carlsson J and Acker H: Relations between pH, oxygen partial pressure and growth in cultured cell spheroids. Int J Cancer. 42:715–720. 1988. View Article : Google Scholar : PubMed/NCBI
36	Khaitan D, Chandna S, Arya MB and Dwarakanath BS: Establishment and characterization of multicellular spheroids from a human glioma cell line; Implications for tumor therapy. J Transl Med. 4:122006. View Article : Google Scholar :
37	Dezonne RS, Sartore RC, Nascimento JM, Saia-Cereda VM, Romão LF, Alves-Leon SV, Souza JM, Martins-de-Souza D, Rehen SK and Gomes FC: Derivation of functional human astrocytes from cerebral organoids. Sci Rep. 7:450912017. View Article : Google Scholar :
38	Siracusa R, Fusco R and Cuzzocrea S: Astrocytes: Role and functions in brain pathologies. Front Pharmacol. 10:11142019. View Article : Google Scholar : PubMed/NCBI
39	Khakh BS and Sofroniew MV: Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 18:942–952. 2015. View Article : Google Scholar
40	Ouyang YB, Xu L, Lu Y, Sun X, Yue S, Xiong XX and Giffard RG: Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia. 61:1784–1794. 2013. View Article : Google Scholar : PubMed/NCBI