title: Potent Inhibition of Nitric Oxide-Releasing Bifendate Derivatives against Drug-Resistant K562/A02 Cells in Vitro and in Vivo.
abstract: Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7a-n) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration and the intracellular accumulation of rhodamine 123 by inhibiting P-gp activity in K562/A02 cells. Furthermore, 7a remarkably down-regulated AKT, NF-κB, and ERK activation and HIF-1α expression in K562/A02 cells, which are associated with the tumor cell proliferation and drug resistance. Notably, the antitumor effects were dramatically attenuated by an NO scavenger or elimination of the NO-releasing capability of 7a, indicating that NO produced by 7a contributed to, at least partly, its cytotoxicity against drug-resistant K562/A02 cells. Overall, 7a may be a potential agent against drug-resistant myelogenous leukemia.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.|Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University , Xuzhou 221004, People's Republic of China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine , Tianjin 300050, People's Republic of China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Rongfang
authors.initials: R
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine , Tianjin 300050, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Institute of Biophysics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical College , Wenzhou 325035, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Yihua
authors.identifier: 0000-0003-2378-7064
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; C465548:bifendate; D009569:Nitric Oxide