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Int J Mol Sci. 2018 Nov 21;19(11). pii: E3684. doi: 10.3390/ijms19113684.

Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy.

Author information

1
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. unyjjo@gmail.com.
2
Department of Bio-Convergence Engineering, Korea University, Seoul 02842, Korea. unyjjo@gmail.com.
3
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. eunhokim8@gmail.com.
4
Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba 263-0024, Japan. sai.sei@qst.go.jp.
5
Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. kjs@kirams.re.kr.
6
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. chojaemin09@naver.com.
7
Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. hyeongi@kirams.re.kr.
8
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. jihan918@kirams.re.kr.
9
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. wjdduql@hanmail.net.
10
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea. sgh63@kcch.re.kr.
11
Department of Bio-Convergence Engineering, Korea University, Seoul 02842, Korea. radioyoon@korea.ac.kr.

Abstract

Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p < 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies.

KEYWORDS:

glioblastoma; sorafenib; tumor-treating fields

PMID:
30469352
PMCID:
PMC6274791
DOI:
10.3390/ijms19113684
[Indexed for MEDLINE]
Free PMC Article

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