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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00942

The natural flavonoid galangin elicits apoptosis, pyroptosis and autophagy in glioblastoma

 Yang Kong1, 2,  Zichao Feng2, 3, Qichao Qi2, 3,  Mingzhi Han2, 3,  Shuai Wang2, 3, Yulin Zhang2, 3, Xin Zhang2, 3, Ning Yang2, 3, Jiwei Wang2, 3, Bin Huang2, 3, Anjing Chen2, 3, Qing Zhang2, 3, Guo Xiang2, 3, Wenjie Li2, 3, Di Zhang2, 3,  Jian Wang2, 3, 4* and Xingang Li1, 2*
  • 1Qilu Hospital, Shandong University, China
  • 2Shandong Provincial Key Laboratory of Brain Function Remodeling, Qilu Hospital, Shandong University, China
  • 3Department of Neurosurgery, Qilu Hospital, Shandong University, China
  • 4Department of Biomedicine, K.G. Jebsen Brain Tumour Research Centre, Faculty of Medicine, University of Bergen, Norway

Galangin (GG), a flavonoid, elicits a potent antitumor activity in diverse cancers. Here, we evaluated the efficacy of GG in the treatment of human glioblastoma multiforme (GBM) and investigated the molecular basis for its inhibitory effects in the disease. GG inhibited viability and proliferation of GBM cells (U251, U87MG and A172) in a dose-dependent manner (IC50 =221.8, 262.5, 273.9 µM, respectively; P < 0.001; EdU, ~ 40% decrease at 150 µM, P < 0.001), and the number of colonies formed was significantly reduced (at 50 µM, P < 0.001). However, normal human astrocytes were more resistant to its cytotoxic effects (IC50 >450 µM). Annexin-V/PI staining was increased indicating that GG induced apoptosis in GBM cells (26.67% and 30.42%, U87MG and U251, respectively) and associated proteins including BAX and cleaved PARP-1 were increased (~ 3×). Cells also underwent pyroptosis as determined under phase-contrast microscopy. Knockdown of gasdermin E (GSDME), a protein involved in pyroptosis, alleviated pyroptosis induced by GG through aggravating nuclear DNA damage in GBM cells. Meanwhile, fluorescent GFP-RFP- MAP1LC3B puncta associated with autophagy increased under GG treatment, and transmission electron microscopy confirmed the formation of autophagic vesicles. Inhibition of autophagy enhanced GG-induced apoptosis and pyroptosis in GBM cells. Finally, in an orthotopic xenograft model in nude mice derived from U87MG cells, treatment with GG in combination with an inhibitor of autophagy, chloroquine, suppressed tumor growth and enhanced survival compared to GG monotherapy (P < 0.05). Our results demonstrated that GG simultaneously induces apoptosis, pytoptosis, and protective autophagy in GBM cells, indicating that combination treatment of GG with autophagy inhibitors may be an effective therapeutic strategy for GBM.

Keywords: Glioblastoma, pyroptosis, Galangin, Autophagy, Apoptosis

Received: 13 May 2019; Accepted: 06 Sep 2019.

Copyright: © 2019 Kong, Feng, Qi, Han, Wang, Zhang, Zhang, Yang, Wang, Huang, Chen, Zhang, Xiang, Li, Zhang, Wang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Jian Wang, Qilu Hospital, Shandong University, Department of Neurosurgery, Jinan, Shandong Province, China, jian.wang@uib.no
PhD. Xingang Li, Qilu Hospital, Shandong University, Jinan, China, lixg@sdu.edu.cn