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  3. Inhibitory effects of flavonoids on glucose transporter 1 (GLUT1): From library screening to biological evaluation to structure-activity relationship

Inhibitory effects of flavonoids on glucose transporter 1 (GLUT1): From library screening to biological evaluation to structure-activity relationship

  • Toxicology. 2023 Mar 2;153475. doi: 10.1016/j.tox.2023.153475.
Yanhong Sun 1,  Xiaoyan Duan 1,  Fenghe Wang 1,  Huixin Tan 1,  Jiahuan Hu 1,  Wanting Bai 1,  Xinbo Wang 1,  Baolian Wang 1,  Jinping Hu 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: hujp@imm.ac.cn.
PMID: 36870413 DOI: 10.1016/j.tox.2023.153475
Abstract

Glucose transporter 1 (GLUT1) is mainly responsible for glucose uptake and energy metabolism, especially in the aerobic glycolysis process of tumor cells, which is closely associated with the advancement of tumors. Numerous studies have demonstrated that the inhibition of GLUT1 can decrease the growth of tumor cells and enhance drug sensitivity, so GLUT1 is considered to be a promising therapeutic target for Cancer treatment. Flavonoids are a group of phenolic secondary metabolites present in vegetables, fruits, and herbal products, some of which were reported to increase Cancer cells' sensitivity to sorafenib by inhibiting GLUT1. Our objective was to screen potential inhibitors of GLUT1 from 98 Flavonoids and assess the sensitizing effect of sorafenib on Cancer cells. and illuminate the structure-activity relationships of Flavonoids with GLUT1. Eight Flavonoids, including apigenin, kaempferol, eupatilin, luteolin, hispidulin, isosinensetin, sinensetin, and nobiletin exhibited significant inhibition (>50%) on GLUT1 in GLUT1-HEK293T cells. Among them, sinensetin and nobiletin showed stronger sensitizing effects and caused a sharp downward shift of the cell viability curves in HepG2 cells, illustrating these two Flavonoids might become sensitizers to enhance the efficacy of sorafenib by inhibiting GLUT1. Molecular docking analysis elucidated inhibitory effect of Flavonoids on GLUT1 was related to conventional hydrogen bonds, but not Pi interactions. The pharmacophore model clarified the critical pharmacophores of Flavonoids inhibitors are hydrophobic groups in 3'positions and hydrogen bond acceptors. Thus, our findings would provide useful information for optimizing flavonoid structure to design novel GLUT1 inhibitors and overcome drug resistance in Cancer treatment.

Keywords

Drug resistance; Flavonoids; Glucose transporter 1; Inhibition; Sorafenib; Structure-activity relationship.

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