The Anti-Glioma Effect of Juglone Derivatives through ROS Generation

Jinsen Zhang; Minjie Fu; Jinfeng Wu; Fengfeng Fan; Xin Zhang; Chunjie Li; Hui Yang; Yonghe Wu; Yiming Yin; Wei Hua

doi:10.3389/fphar.2022.911760

The Anti-Glioma Effect of Juglone Derivatives through ROS Generation

Front Pharmacol. 2022 Jun 14:13:911760. doi: 10.3389/fphar.2022.911760. eCollection 2022.

Authors

Jinsen Zhang^{1

2

3

4

5}, Minjie Fu^{1

2

3

4

5}, Jinfeng Wu⁶, Fengfeng Fan^{1

2

3

4

5}, Xin Zhang^{1

2

3

4

5}, Chunjie Li¹, Hui Yang^{1

2

3

4

5}, Yonghe Wu⁷, Yiming Yin⁸, Wei Hua^{1

2

3

4

5}

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
² National Center for Neurological Disorders, Shanghai, China.
³ Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China.
⁴ Neurosurgical Institute of Fudan University, Shanghai, China.
⁵ Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China.
⁶ Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
⁷ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
⁸ Departmeng of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Abstract

Juglone has been extensively reported as a natural antitumor pigment. However, it is easy to be oxidized due to active hydroxy in the quinone. Here, we designed some new juglone derivatives, as the hydroxy was replaced by methyl (D1), allyl (D2), butyl (D3), and benzyl (D4) groups. Nuclear magnetic resonance spectra and mass spectrometry were applied to confirm the derivatives and oxidative products of juglone. U87 and U251 cell lines were used for tests in vitro, and primary human glioblastoma cells were applied for in vivo experiments. The CCK8 and EdU assay demonstrated the anti-tumor effect of the four derivatives, and IC50 for U87 was 3.99, 3.28, 7.60, and 11.84 μM, respectively. In U251, IC50 was 7.00, 5.43, 8.64, and 18.05 μM, respectively. D2 and D3 were further selected, and flow cytometry showed that apoptosis rates were increased after D2 or D3 treatment via ROS generation. Potential targets were predicted by network pharmacology analysis, most of which were associated with apoptosis, cell cycle, and metabolism pathway. CDC25B and DUSP1 were two of the most likely candidates for targets. The orthotopic glioblastoma model was established to evaluate the anti-glioma effect and side-effect of juglone derivatives, and the in vivo experiments confirmed the anti-glioma effects of juglone derivatives. In conclusion, new derivatives of juglone were created via chemical group substitution and could inhibit glioma cell viability and proliferation and induce apoptosis rate via ROS generation.

Keywords: ROS; apoptosis; chemotherapy; glioblastoma; juglone.