title: Discovery of New Monocarbonyl Ligustrazine-Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer.
abstract: The elevation of oxidative stress preferentially in cancer cells by inhibiting thioredoxin reductase (TrxR) and/or enhancing reactive oxygen species (ROS) production has emerged as an effective strategy for selectively targeting cancer cells. In this study, we designed and synthesized 21 ligustrazine-curcumin hybrids (10a-u). Biological evaluation indicated that the most active compound 10d significantly inhibited the proliferation of drug-sensitive (A549, SPC-A-1, LTEP-G-2) and drug-resistant (A549/DDP) lung cancer cells but had little effect on nontumor lung epithelial-like cells (HBE). Furthermore, 10d suppressed the TrxR/Trx system and promoted intracellular ROS accumulation and cancer cell apoptosis. Additionally, 10d inhibited the NF-κB, AKT, and ERK signaling, P-gp-mediated efflux of rhodamine 123, P-gp ATPase activity, and P-gp expression in A549/DDP cells. Finally, 10d repressed the growth of implanted human drug-resistant lung cancer in mice. Together, 10d acts a novel TrxR inhibitor and may be a promising candidate for intervention of lung cancer.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ai
authors.affiliation: Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Sciences, Central South University , Changsha 410078, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Sciences, Central South University , Changsha 410078, China.
authors.forename: Caiping
authors.initials: C
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Kang
authors.affiliation: Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Sciences, Central South University , Changsha 410078, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California , Los Angeles, California 90095, United States.
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013880:Thioredoxin-Disulfide Reductase; D003474:Curcumin; C017953:tetramethylpyrazine