The Natural Flavonoid Galangin Elicits Apoptosis, Pyroptosis, and Autophagy in Glioblastoma.

Yang Kong,Ning Yang,Anjing Chen,Xingang Li,Bin Huang,Shuai Wang,Xin Zhang,Yulin Zhang,Jiwei Wang,Zichao Feng,Mingzhi Han,Wenjie Li,Guo Xiang,Qing Zhang,Di Zhang,Jian Wang,Qichao Qi

doi:10.3389/fonc.2019.00942

The Natural Flavonoid Galangin Elicits Apoptosis, Pyroptosis, and Autophagy in Glioblastoma.

Yang Kong, Ning Yang + Show 15 more

Open Access

https://doi.org/10.3389/fonc.2019.00942

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Abstract

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.

Highlights

Glioblastoma multiforme (GBM) is the most common and deadly primary malignant tumor of the central nervous system in humans
Normal human astrocytes (NHA) were more resistant to treatment with increasing concentrations of GG, indicating that GG might be selective for tumor cells at certain concentrations
EdU incorporation was reduced in a dose-dependent manner in both U251 and U87MG cells treated with increasing concentrations of GG, indicating that the molecule inhibited cell proliferation (Figure 1C)

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and deadly primary malignant tumor of the central nervous system in humans. Median survival is 15–23 months [1], which is in part due to several biological properties rendering the tumor type resistant to current therapeutic modalities. Galangin Elicits Apoptosis, Pyroptosis, Autophagy the absorption of drugs [2]. GBM cells have an intrinsic resistance to the induction of cell death [3, 4]. The current therapeutic schedule is aggressive, including surgical resection, temozolomide (TMZ), and concurrent adjuvant radiation therapy [6], and yet, this strategy only delays tumor progression. It causes significant adverse reactions reducing patient quality of life.

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