title: The overexpression and nuclear translocation of Trx-1 during hypoxia confers on HepG2 cells resistance to DDP, and GL-V9 reverses the resistance by suppressing the Trx-1/Ref-1 axis.
abstract: Microenvironmental hypoxia gives many tumor cells the capacity for drug resistance. Thioredoxin family members play critical roles in the regulation of cellular redox homeostasis in a stressed environment. In this study, we established a hypoxia-drug resistance (hypoxia-DR) model using HepG2 cells and discovered that the overexpression and nuclear translocation of thioredoxin-1 (Trx-1) are closely associated with this resistance through the regulation of the metabolism by the oxidative stress response to glycolysis. Intranuclear Trx-1 enhances the DNA-binding activity of HIF-1α via its interaction with and reducing action on Ref-1, resulting in increased expression of glycolysis-related proteins (PDHK1, HKII, and LDHA), glucose uptake, and lactate generation under hypoxia. Meanwhile, we found that GL-V9, a newly synthesized flavonoid derivative, shows an ability to reverse the hypoxia-DR and has low toxicity both in vivo and in vitro. GL-V9 could inhibit the expression and nuclear translocation of Trx-1 and then suppress HIF-1α DNA-binding activity by inhibiting the Trx-1/Ref-1 axis. As a result, glycolysis is weakened and oxidative phosphorylation is enhanced. Thus, GL-V9 leads to an increment in intracellular ROS generation and consequently intensified apoptosis induced by DDP.
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education.
authors: Li
authors: L
authors: Zhao
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education.
authors: Wei
authors: W
authors: Li
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education.
authors: Yuxin
authors: Y
authors: Zhou
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education.
authors: Yi
authors: Y
authors: Zhang
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education.
authors: Shaoliang
authors: S
authors: Huang
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education.
authors: Xuefen
authors: X
authors: Xu
authors: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People׳s Republic of China.
authors: Zhiyu
authors: Z
authors: Li
authors: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Design and Optimization, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education. Electronic address: anticancer_drug@163.com.
authors: Qinglong
authors: Q
authors: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology; D011768:Pyruvate Dehydrogenase Complex / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C561826:5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl)butoxy)4H-chromen-4-one; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005419:Flavonoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C045867:PDHX protein, human; D011768:Pyruvate Dehydrogenase Complex; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D019344:Lactic Acid; D013879:Thioredoxins; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D005947:Glucose; D002945:Cisplatin
keywords: Free radicals; GL-V9; Hypoxia-DR; ROS; Reverse; Trx-1/Ref-1 axis