Abstract
The use of electric field for cancer therapy has been proposed for a novel non-invasive cancer therapeutic approach that provides better quality of life for patients. However, argument of the efficacy hampers the therapeutic development for various cancer diseases. More scientific evidences are necessary to be addressed by basic research. The current in vitro cell culture study reports the responses of tumor spheroids after the application of an alternating electric field. Human hepatocarchinoma cells suspended in soft hydrogel were cultured in a cell culture device embedded with stimulating electrodes. Tumor spheroids gradually formed and alternating electric field was then applied during the culture course. Investigation of cell viability and cell cycle were conducted to optimize the treatment conditions. The results showed that the electric potential of 1.0 Vpp and frequency of 130 kHz was the minimal effective conditions for inhibiting tumor spheroids. Importantly, dissociation of tumor spheroids was observed after the treatment. The effectiveness of chemotherapeutic agents was shown to be enhanced while the electric filed was simultaneously applied to the tumor spheroids. These results provided solid foundation for developing the effective therapeutic strategies.
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References
A. Abbott, Cell culture: biology’s new dimension. Nature 424, 870–872 (2003)
D.O. Draper, K. Knight, T. Fujiwara, J.C. Castel, Temperature change in human muscle during and after pulsed short-wave diathermy. J. Orthop. Sports Phys. Ther. 29, 13–22 (1999)
R.A. El-Awady, M.H. Semrren, M.M. Saber-Ayad, F. Cyprian, V. Menon, et al., Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells. DNA Repair 37, 1–11 (2016)
N. Gera, A. Yang, T.S. Holtzman, S.X. Lee, E.T. Wong, et al., Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS One 10, e125269 (2015)
M. Giladi, U. Weinberg, R.S. Schneiderman, Y. Porat, M. Munster, et al., Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin. Oncol. 41, S35–S41 (2014)
M. Giladi, R.S. Schneiderman, T. Voloshin, Y. Porat, M. Munster, et al., Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci. Rep. 5, 18046 (2015)
S.N. Goldberg, Radiofrequency tumor ablation: Principles and techniques. Eur. J. Ultrasound 13, 129–147 (2001)
C. Goldstein, S. Sprague, B.A. Petrisor, Electrical stimulation for fracture healing: Current evidence. J. Orthop. Trauma 24, S62–S65 (2010)
M. Hay, D.W. Thomas, J.L. Craighead, C. Economides, J. Rosenthal, Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 (2014)
T. Inui, H. Amitani, K. Kubo, D. Kuchiike, Y. Uto, et al., Case report: A non-small cell lung cancer patient treated with GcMAF, sonodynamic therapy and tumor treating fields. Anticancer Res. 36, 3767–3770 (2016)
T.E. Jorgensen, Electrical stimulation of human fracture healing by means of a slow pulsating, asymmetrical direct current. Clin. Orthop. Relat. Res. 124, 124–127 (1977)
N.K. Karanam, K. Srinivasan, L. Ding, B. Sishc, D. Saha, et al., Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis. 8, e2711 (2017)
E.H. Kim, Y.J. Kim, H.S. Song, Y.K. Jeong, J.Y. Lee, et al., Biological effect of an alternating electric field on cell proliferation and synergistic antimitotic effect in combination with ionizing radiation. Oncotarget 7, 62267–62279 (2016)
E.D. Kirson, Z. Gurvich, R. Schneiderman, E. Dekel, A. Itzhaki, et al., Disruption of Cancer cell replication by alternating electric fields. Cancer Res. 64, 3288–3295 (2004)
E.D. Kirson, V. Dbaly, F. Tovarys, J. Vymazal, J.F. Soustiel, et al., Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc. Natl. Acad. Sci. U. S. A. 104, 10152–10157 (2007)
E.D. Kirson, R.S. Schneiderman, V. Dbaly, F. Tovaryš, J. Vymazal, et al., Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med. Phys. 9, 1 (2009)
V. Koshkin, L.E. Ailes, G. Liu, S.N. Krylov, Metabolic suppression of a drug-resistant subpopulation in cancer spheroid cells. J. Cell. Biochem. 117, 59–65 (2016)
R. Kunjithapatham, S. Karthikeyan, J.-F. Geschwind, E. Kieserman, M.D. Lin, et al., Reversal of anchorage-independent multicellular spheroid into a monolayer mimics a metastatic model. Sci. Report. 4, 6816
T.K.W. Lee, T.C.M. Lau, I.O.L. Ng, Doxorubicin-induced apoptosis and chemosensitivity in hepatoma cell lines. Cancer Chemother. Pharmacol. 49, 78–86 (2002)
J. Lee, M.J. Cuddihy, N.A. Kotov, Three-dimensional cell culture matrices: State of the art. Tissue Eng. 14, 61–86 (2008)
R.Z. Lin, H.Y. Chang, Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol. J. 3, 1172–1184 (2008)
J. Liu, Y. Tan, H. Zhang, Y. Zhang, P. Xu, et al., Soft fibrin gels promote selection and growth of tumorigenic cells. Nat. Mater. 11, 734–741 (2012)
S. Okada, Chemotherapy in hepatocellular carcinoma. Hepato-Gastroenterology 45(Suppl 3), 1259–1263 (1998)
P.L. Olive, R.E. Durand, Drug and radiation resistance in spheroids: Cell contact and kinetics. Cancer Metastasis Rev. 13, 121–138 (1994)
A. Pavesi, G. Adriani, A. Tay, M.E. Warkiani, W.H. Yeap, et al., Engineering a 3D microfluidic culture platform for tumor-treating field application. Sci. Rep. 6, 26584 (2016)
M. Pless, U. Weinberg, Tumor treating fields: Concepts, evidence and future. Expert Opin. Investig. Drugs 20, 1099–1106 (2011)
M. Pless, C. Drogege, R. von Moss, M. Salzberg, D. Betticher, A phase I/II trial of tumor treating fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer 81, 445–450 (2013)
R.S. Schneiderman, E. Shmueli, E.D. Kirson, Y. Palti, TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters. BMC Cancer 10, 229 (2010)
K.A. Sluka, D. Walsh, Transcutaneous electrical nerve stimulation: Basic science mechanisms and clinical effectiveness. J. Pain 4, 109–121 (2003)
R. Stupp, E.T. Wong, A.A. Kanner, D. Steinberg, H. Engelhard, 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)
J. Terashima, S. Goto, H. Hattori, S. Hoshi, M. Ushirokawa, et al., CYP1A1 and CYP1A2 expression levels are differentially regulated in three-dimensional spheroids of liver cancer cells compared to two-dimensional monolyaer cultures. Drug Metab. Pharmacokinet. 30, 434–440 (2015)
T. Voloshin, M. Munster, R. Blatt, A. Shteingauz, P.C. Roberts, et al., Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo. Int. J. Cancer 139, 2850–2858 (2016)
J. Vymazal, E.T. Wong, Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin. Oncol. 41, S14–S24 (2014)
E.T. Wong, E. Lok, K.D. Swanson, S. Gautam, H.H. Engelhard, et al., Response assessment of NovoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma. Cancer Med. 3, 592–602 (2014)
Z. Zhu, X. Hao, M. Yan, M. Yao, C. Ge, et al., Cancer stem/progenitor cells are highly enriched in CD133+ CD44+ population in hepatocellular carcinoma. Int. J. Cancer 126, 2067–2078 (2010)
Acknowledgements
The authors would like to thank Ms. Sandy Huang for her technical support. This work was supported by Chang Gung Memorial Hospital, Linkou, Taiwan (Project no. CMRPD2H0021 and BMRPC05).
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Huang, CH., Lei, K.F. & Tsang, NM. Dissociated effect and Chemosensitive enhancement of tumor spheroids influenced by an electric field in a microdevice. Biomed Microdevices 20, 70 (2018). https://doi.org/10.1007/s10544-018-0316-2
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DOI: https://doi.org/10.1007/s10544-018-0316-2