Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy
<p>Tumor-treating field (TTField)-sensitizing effects of sorafenib on in vitro models of glioblastoma. (<b>A</b>) TTFields inhibited glioblastoma cell viability in an intensity-dependent manner. Cell viability was evaluated by cell counting using 0.4% Trypan Blue stain for U373 and U87 cells treated with TTFields for the indicated durations; * <span class="html-italic">p</span> < 0.05; (<b>B</b>) sorafenib inhibited glioblastoma cell Fluorine-18viability in a dose-dependent manner. Cell viability was evaluated by cell counting using 0.4% Trypan Blue stain for U373 and U87 cells treated with the indicated doses of sorafenib; * <span class="html-italic">p</span> < 0.05. (<b>C</b>–<b>E</b>) the viability of cells treated with a combination of TTFields and sorafenib was significantly lower than that of cells treated with either sorafenib or TTFields. The proliferation rate was detected by counting (<b>C</b>), MTT assay (<b>D</b>), and 3D colony culture (<b>E</b>). * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; (<b>F</b>) the sensitivity of U373 and U87 cells treated with sorafenib and TTFields was measured via a colony formation assay. The survival fraction, which was expressed as a function of the irradiation dose, was calculated as follows: survival fraction = colonies counted/(cells seeded × plating efficiency/100). * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01. CTL: Control group; TTF: Tumor treating fields group.</p> "> Figure 2
<p>Tumor-treating field (TTField)-sensitizing effects of sorafenib on glioblastoma in vivo. (<b>A</b>) Nude mice were inoculated with U373 cells and treated with TTFields, sorafenib, or a combination thereof. Tumor volumes were measured at the indicated time points, using the formula: volume = (length × width<sup>2</sup> × 3.14)/6 (<span class="html-italic">n</span> = 8); * <span class="html-italic">p</span> < 0.05; (<b>B</b>) images of tumors isolated from control- or TTFields-treated mice, <span class="html-italic">n</span> = 4, Sora: sorafenib.; bar = 1 cm (<b>C</b>) tumors were excised and weighed at the end of the experiment (seven days). * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; (<b>D</b>) representative PET/CT images of U373 tumor-bearing mice after injection of [<sup>18</sup>F]-fluorodeoxyglucose (FDG). The radioactivity of [<sup>18</sup>F]-FDG in tumors is presented as the maximum standard uptake value (mean ± SD). * <span class="html-italic">p</span> < 0.05; SUV: Standard uptake value. (<b>E</b>) hematoxylin and eosin (H&E) staining and Ki-67 expression was examined by immunohistochemistry. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01, <span class="html-italic">n</span> = 4; Solid circle: Control; Solid square: Sorafenib; Triangle: Tumor treating fields; Inverted triangle: Sorafenib+TTF. (<b>F</b>) the body weights of the mice were not significantly different among the sorafenib-, TTFields-, and combination-treated groups, <span class="html-italic">n</span> = 4; (<b>G</b>) the spleen, liver, and lung tissues of the mice were excised and weighed at the end of the experiment (seven days), <span class="html-italic">n</span> = 4.</p> "> Figure 3
<p>Effects of sorafenib and tumor-treating fields (TTFields) on apoptosis in glioblastoma cells. (<b>A</b>) U373 and U87 cells were exposed to sorafenib (5 µmol/L) and/or TTFields for 48 h prior to annexin V/PI staining; (<b>B</b>) cell lysates (30 µg) were immunoblotted with antibodies against cleaved PARP1 and β-actin; Band intensities were quantified and normalized to actin intensities (<span class="html-italic">n</span> = 3, mean ± SD). (<b>C</b>) terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assays were performed using xenografts, <span class="html-italic">n</span> = 4; Solid circle: Control; Solid square: Sorafenib; Triangle: Tumor treating fields; Inverted triangle: Sorafenib+TTF. (<b>D</b>,<b>E</b>) U373 and U87 cells were treated with sorafenib, TTFields, or the indicated combinations, and reactive oxygen species (ROS) levels were determined using 2′,7′-dichlorofluorescein diacetate (a peroxide-sensitive dye), flow cytometry, and confocal laser fluorescence microscopy. Data are expressed as % of control and are means ± SD from 3 experiments. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 4
<p>Combinatorial treatment with sorafenib and tumor-treating fields (TTFields) induces autophagy in glioblastoma cancer cells. (<b>A</b>) cell lysates (30 µg) were immunoblotted with anti-LC3 and anti-β-actin antibodies; Band intensities were quantified and normalized to actin intensities (<span class="html-italic">n</span> = 3, mean ± SD). (<b>B</b>) cyto-ID staining of U373 and U87 cells with and without sorafenib or with and without TTFields treatment. ** <span class="html-italic">p</span> < 0.01; (<b>C</b>) cells were stained with Giemsa stain (10% in phosphate-buffered saline), washed, and imaged using a Leica DM IRB light microscope (magnification, 40×). Black arrows indicate vacuoles. ** <span class="html-italic">p</span> < 0.01; (<b>D</b>) autophagy was assessed by transmission electron microscopy in cells, bar = 1 µm; black arrow: autophagic vacuoles. (<b>E</b>) LC3 expression in xenografts was examined by immunohistochemistry. Representative images are presented. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; <span class="html-italic">n</span> = 4; Solid circle: Control; Solid square: Sorafenib; Triangle: Tumor treating fields; Inverted triangle: Sorafenib+TTF.</p> "> Figure 5
<p>Sorafenib plus tumor-treating fields (TTFields) inhibits cell cycle progression in glioblastoma cells. (<b>A</b>) U373 and U87 cells were treated with sorafenib (5 µmol/L) and/or 0.9 V/cm TTFields for 24 h. Cell cycle distribution was analyzed quantitatively by flow cytometry. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; (<b>B</b>) phospho-cdc2 and cyclin B1 expression was analyzed by Western blotting. β-Actin served as a loading control. Equal amounts of cell lysate (30 µg) were electrophoresed and analyzed; Band intensities were quantified and normalized to actin intensities (<span class="html-italic">n</span> = 3, mean ± SD).</p> "> Figure 6
<p>Effect of combinatorial treatment with Sorafenib and tumor-treating fields (TTFields) on the invasiveness and migration of glioblastoma cells. (<b>A</b>) tumor cell migration was assessed using a Transwell chamber assay. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01, bar = 500 µm; (<b>B</b>) tumor cell invasion was assessed using a Matrigel invasion assay. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01, bar = 500 µm; (<b>C</b>) cell lysates prepared from sorafenib-, TTFields-, and sorafenib plus TTFields-treated cells were used in Western blotting using antibodies against vimentin and fibronectin; Band intensities were quantified and normalized to actin intensities (<span class="html-italic">n</span> = 3, mean ± SD). (<b>D</b>) tube formation assay using 2H11 cells subjected to the indicated treatments; (<b>E</b>) 3D colony cultures of 2H11 cells treated as indicated. ** <span class="html-italic">p</span> < 0.01.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Cooperative Effect of TTFields and Sorafenib on Glioblastoma Cancer Cell Proliferation
2.2. Sorafenib Promotes TTFields Sensitivity In Vivo
2.3. Sorafenib Enhances TTFields-Induced Apoptosis
2.4. Effects of Sorafenib and TTFields on Autophagic Cell Death
2.5. Effects of Sorafenib and TTFields on the Cell Cycle
2.6. Combinatorial Treatment Significantly Inhibits Tumor Cell Motility and Invasion, and Angiogenesis
3. Discussion
4. Materials and Methods
4.1. Experimental Setup for Electric Fields
4.2. Antibodies and Chemicals
4.3. Cell Culture
4.4. Cell Viability Assay
4.5. 3D Culture System
4.6. Colony Formation Assay
4.7. Tumor Xenografts in Nude Mice
4.8. Positron Emission Tomography (PET)/Computed Tomography (CT) Acquisition
4.9. Detection of Apoptotic Cells via Annexin V Staining
4.10. Western Blotting
4.11. TUNEL Assay
4.12. Fluorescence-Based Quantification of Intracellular ROS
4.13. Autophagy Assay
4.14. Giemsa Staining
4.15. Transmission Electron Microscopy
4.16. Immunohistochemistry
4.17. Flow Cytometry
4.18. Invasion/Migration Assay
4.19. Matrigel-Based In Vitro Endothelial Tube Formation Assay
4.20. Statistical Analysis
Author Contributions
Funding
Conflicts of Interest
References
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Jo, Y.; Kim, E.H.; Sai, S.; Kim, J.S.; Cho, J.-M.; Kim, H.; Baek, J.-H.; Kim, J.-Y.; Hwang, S.-G.; Yoon, M. Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy. Int. J. Mol. Sci. 2018, 19, 3684. https://doi.org/10.3390/ijms19113684
Jo Y, Kim EH, Sai S, Kim JS, Cho J-M, Kim H, Baek J-H, Kim J-Y, Hwang S-G, Yoon M. Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy. International Journal of Molecular Sciences. 2018; 19(11):3684. https://doi.org/10.3390/ijms19113684
Chicago/Turabian StyleJo, Yunhui, Eun Ho Kim, Sei Sai, Jin Su Kim, Jae-Min Cho, Hyeongi Kim, Jeong-Hwa Baek, Jeong-Yub Kim, Sang-Gu Hwang, and Myonggeun Yoon. 2018. "Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy" International Journal of Molecular Sciences 19, no. 11: 3684. https://doi.org/10.3390/ijms19113684