title: Anticancer efficacy of a nitric oxide-modified derivative of bifendate against multidrug-resistant cancer cells.
abstract: The development of multidrug resistance (MDR) not only actively transports a wide range of cytotoxic drugs across drug transporters but is also a complex interaction between a number of important cellular signalling pathways. Nitric oxide donors appear to be a new class of anticancer therapeutics for satisfying all the above conditions. Previously, we reported furoxan-based nitric oxide-releasing compounds that exhibited selective antitumour activity in vitro and in vivo. Herein, we demonstrate that bifendate (DDB)-nitric oxide, a synthetic furoxan-based nitric oxide-releasing derivative of bifendate, effectively inhibits the both sensitive and MDR tumour cell viability at a comparatively low concentration. Interestingly, the potency of DDB-nitric oxide is the independent of inhibition of the functions and expressions of three major ABC transporters. The mechanism of DDB-nitric oxide appears to be in two modes of actions by inducing mitochondrial tyrosine nitration and apoptosis, as well as by down-regulating HIF-1α expression and protein kinase B (AKT), extracellular signal-regulated kinases (ERK), nuclear factor κB (NF-κB) activation in MDR cells. Moreover, the addition of a typical nitric oxide scavenger significantly attenuated all the effects of DDB-nitric oxide, indicating that the cytotoxicity of DDB-nitric oxide is as a result of higher levels of nitric oxide release in MDR cancer cells. Given that acquired MDR to nitric oxide donors is reportedly difficult to achieve and genetically unstable, compound like DDB-nitric oxide may be a new type of therapeutic agent for the treatment of MDR tumours.
authors: Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine, Beijing, China.|Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors: Zhiguang
authors: Z
authors: Ren
authors: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors: Xiaoke
authors: X
authors: Gu
authors: School of Laboratory Medicine and Life Science, Wenzhou Medical College, Wenzhou, China.
authors: Bin
authors: B
authors: Lu
authors: Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors: Yaqiong
authors: Y
authors: Chen
authors: Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors: Guojiang
authors: G
authors: Chen
authors: Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors: Jiannan
authors: J
authors: Feng
authors: Department of Otolaryngology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors: Jizhen
authors: J
authors: Lin
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors: Yihua
authors: Y
authors: Zhang
authors: Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine, Beijing, China.|Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors: Hui
authors: H
authors: Peng
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; C465548:bifendate; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: anticancer; bifendate; multidrug resistance; nitric oxide