Quercetin induces MGMT⁺ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways

Wang, Wanyu1,2; Yuan, Xiaopeng3; Mu, Jiasheng4,5; Zou, Yuheng2; Xu, Lanyang; Chen, Jiali2; Zhu, Xiao2; Li, Biaoping2; Zeng, Zhiyun2; Wu, Xianghui6; Yin, Zhixin2; Wang, Qirui1,2

2023-09-01

10.1016/j.phymed.2023.154933

PHYTOMEDICINE   影响因子和分区

0944-7113

1618-095X

["Background: Surgical resection combined with radiotherapy and chemotherapy remains a common clinical treatment for glioblastoma multiforme (GBM). However, the therapeutic outcomes have not been satisfying due to drug resistance and other factors. Quercetin, a phytoingredient capable of crossing the blood-brain barrier, has shown effectiveness in the treatment of various solid tumors. Nevertheless, the potential of quercetin in GBM treatment has not been adequately explored.","Purpose: This study aims to investigate the effects and mechanisms of quercetin on MGMT(+)GBM cells.","Methods: The potential targets and mechanisms of quercetin in glioma treatment were predicted based on network pharmacology and molecular docking. The effects of quercetin on cell inhibition rate, cell migration ability, cell cycle arrest, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), Mitochondrial superoxide formation and apoptosis were measured by the CCK8 assay, wound healing assay, PI/RNase staining, JC-1 assay, DCFH-DA assay, MitoSOX staining and Annexin V-FITC/PI double staining, respectively. The methylation status of the MGMT promoter was assessed through methylation-specific polymerase chain reaction (MS-PCR). DNA damage was quantified by alkaline/neutral comet assay and TUNEL assay. The intracellular localization and expression of NF-kappa B and MGMT were revealed by immunofluorescence. The expression of migration-related proteins, matrix metalloproteinases, apoptosis-related proteins, cyclins, DNA damage/repair enzymes and related pathway proteins was detected by Western blot.","Results: Network pharmacology identified 96 targets and potential molecular mechanisms of quercetin in glioma treatment. Subsequent experiments confirmed the synergistic effect of quercetin in combination with temozolomide (TMZ) on T98G cells. Quercetin significantly suppressed the growth and migration of human GBM T98G cells, induced apoptosis, and arrested cells in the S-phase cell cycle. The collapse of mitochondrial membrane potential, ROS generation, enhanced Bax/Bcl-2 ratio, and strengthened cleaved-Caspase 9 and cleaved-Caspase 3 suggested the involvement of ROS-mediated mitochondria-dependent apoptosis in the process of quercetin-induced apoptosis. In addition, quercetin-induced apoptosis was accompanied by intense DNA double-strand breaks (DSBs), gamma H2AX foci formation, methylation of MGMT promoter, increased cleaved-PARP, and reduced MGMT expression. Quercetin may influence the expression of the key DNA repair enzyme, MGMT, by dual suppression of the Wnt3a/beta-Catenin and the Akt/NF-kappa B signaling pathways, thereby promoting apoptosis. Inhibition of Wnt3a and Akt using specific inhibitors hindered MGMT expression.","Conclusion: Our study provides the first evidence that quercetin may induce apoptosis in MGMT(+)GBM cells via dual inhibition of the Wnt3a/beta-Catenin pathway and the Akt/NF-kappa B signaling pathway. These findings suggest that quercetin could be a novel agent for improving GBM treatment, especially in TMZ-resistant GBM with high MGMT expression."]

Glioblastoma Quercetin MGMT Wnt3a/beta-Catenin signaling pathway Akt/NF-kappa B signaling pathway

SCI

英语

其他

National Natural Science Foundation of China["82074337","81873295"] ; Natural Science Foundation of Guang-dong Province["2023A1515010937","2019A1515012209","2018A030313106"] ; Guangzhou Science and Technology Programme[202201010862]

Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine

Plant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:001048467000001

ELSEVIER GMBH

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Southern Med Univ, Zhujiang Hosp, Guangzhou 510282, Guangdong, Peoples R China
2.Southern Med Univ, Sch Tradit Chinese Med, Dept Mol Biol, State Adm Tradit Chinese Med Peoples Republ China, Guangzhou 510515, Guangdong, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Dept Clin Lab, Shenzhen 518020, Guangdong, Peoples R China
4.Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gen Surg, Shanghai 200092, Peoples R China
5.Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Biliary Tract Dis Res, Shanghai 200092, Peoples R China
6.Southern Med Univ, Nanfang Hosp, Guangzhou 510515, Guangdong, Peoples R China

Wang, Wanyu,Yuan, Xiaopeng,Mu, Jiasheng,et al. Quercetin induces MGMT⁺ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways[J]. PHYTOMEDICINE,2023,118.

Wang, Wanyu.,Yuan, Xiaopeng.,Mu, Jiasheng.,Zou, Yuheng.,Xu, Lanyang.,...&Wang, Qirui.(2023).Quercetin induces MGMT⁺ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways.PHYTOMEDICINE,118.

Wang, Wanyu,et al."Quercetin induces MGMT⁺ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways".PHYTOMEDICINE 118(2023).