Low-intensity ultrasound combined with arsenic trioxide induced apoptosis of glioma via EGFR/AKT/mTOR

Yi Fang; Zhiqun Bai; Jibin Cao; Gaosen Zhang; Xiang Li; Shufeng Li; Yudie Yan; Peirong Gao; Xiangkai Kong; Zhen Zhang

doi:10.1016/j.lfs.2023.122103

Low-intensity ultrasound combined with arsenic trioxide induced apoptosis of glioma via EGFR/AKT/mTOR

Life Sci. 2023 Nov 1:332:122103. doi: 10.1016/j.lfs.2023.122103. Epub 2023 Sep 18.

Authors

Yi Fang¹, Zhiqun Bai¹, Jibin Cao², Gaosen Zhang¹, Xiang Li¹, Shufeng Li¹, Yudie Yan¹, Peirong Gao³, Xiangkai Kong⁴, Zhen Zhang⁵

Affiliations

¹ Department of Ultrasound, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
² Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
³ Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
⁴ Department of Ultrasound, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China.
⁵ Department of Ultrasound, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China. Electronic address: zhangzhen@cmu.edu.cn.

PMID: 37730111
DOI: 10.1016/j.lfs.2023.122103

Abstract

Aims: This study aimed to explore whether low-intensity ultrasound (LIUS) combined with low-concentration arsenic trioxide (ATO) could inhibit the proliferation of glioma and, if so, to clarify the potential mechanism.

Main methods: The effects of ATO and LIUS alone or in combination on glioma were examined by CCK8, EdU, and flow cytometry assays. Western blot analysis was used to detect changes in expression of apoptosis-related proteins and their effects on the EGFR/AKT/mTOR pathway. The effects of ATO and LIUS were verified in vivo in orthotopic xenograft models, and tumor size, arsenic content in brain tissue, survival, and immunohistochemical changes were observed.

Key findings: LIUS enhanced the inhibitory effect of ATO on the proliferation of glioma, and EGF reversed the proliferation inhibition and protein changes induced by ATO and LIUS. The anti-glioma effect of ATO combined with LIUS was related to downstream AKT/mTOR pathway changes caused by inhibition of EGFR activation, which enhanced apoptosis of U87MG and U373 cells. In vivo experiments showed significant increases in arsenic content in brain tissue, as well as decreased tumor sizes and longer survival times in the combined treatment group compared with other groups. The trends of immunohistochemical protein changes were consistent with the in vitro results.

Significance: This study showed that LIUS enables ATO to exert anti-glioma effects at a safe dose by inhibiting the activation of EGFR and the downstream AKT/mTOR pathway to regulate apoptosis. LIUS in combination with ATO is a promising novel method for treating glioma and could improve patient prognosis.

Keywords: Apoptosis; Arsenic trioxide; EGFR; Glioma; Low-intensity ultrasound.