Nitensidine A,a guanidine alkaloid from Pterogyne nitens,is a novel substrate for human ABC transporter ABCB1 |
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| Institution: | 1. Department of Applied Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan;2. Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan;3. Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany;4. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany;5. Department of Organic Chemistry, Institute of Chemistry, São Paulo State University, 355, 14800-900 Araraquara, Brazil;6. Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan;1. Univ. de Bordeaux, Laboratoire d‘Immunologie, INSERM U1035, Faculté de Pharmacie, F-33076 Bordeaux, France;2. Univ. de Bordeaux, ISVV, Polyphénols Biotech, Groupe d‘Etude des Substances Végétales à Activité Biologique, EA 3675, F-33140 Villenave d‘Ornon, France;1. Department of Geriatric Gastroenterology, the First Affiliated Hospital to Nanjing Medical University, Nanjing 210029, PR China;2. Department of Respiratory Medicine, the Affiliated Nanjing Children Hospital to Nanjing Medical University, Nanjing 210029, PR China;3. Department of Pharmacy, the First Affiliated Hospital to Nanjing Medical University, Nanjing 210029, PR China;4. Department of Oncology, the First Affiliated Hospital to Nanjing Medical University, Nanjing 210029, PR China;1. Laboratório de Farmacologia e Imunidade, Centro de Ciências Biológicas, Universidade Federal de Alagoas, 57020-720 Maceió, AL, Brazil;2. Laboratório de Fitoquímica e Química Medicinal (LFQM), Instituto de Química, Universidade Federal de Alfenas, 37130-000 Alfenas, MG, Brazil;3. Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE), Instituto de Química, Universidade Estadual Paulista, 14801-970 Araraquara, São Paulo, Brazil;1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, UP, India;2. Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226 001, UP, India;1. State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Enginnering (Tianjin), NanKai University, Tianjian 300071, PR China;2. College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, PR China;1. Departamento de Química, Universidade Federal de Lavras, C.P. 3037, Lavras, MG CEP 37.200-000, Brazil;2. Instituto de Química, Universidade Estadual Paulista Júlio de Mesquita Filho, Araraquara, SP CEP 14.800-900, Brazil;3. Empresa de Pesquisa Agropecuária de Minas Gerais, Universidade Federal de Lavras, C.P. 3037, Lavras, MG CEP 37.200-000, Brazil |
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| Abstract: | The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibited some level of cytotoxicity against both CCRF-CEM and CEM/ADR5000 cells. In ATPase assays, three of the four guanidine alkaloids were found to stimulate the ATPase activity of ABCB1. Notably, nitensidine A was clearly found to stimulate the ATPase activity of ABCB1 as strongly as the control drug, verapamil. Furthermore, the cytotoxic effect of nitensidine A on CEM/ADR5000 cells was synergistically enhanced by verapamil. Nitensidine A inhibited the extrusion of calcein by ABCB1. In the present study, the possibility of interaction between ABCB1 and two synthetic nitensidine A analogs (nitensidine AT and AU) were examined to gain insight into the mechanism by which nitensidine A stimulates the ATPase activity of ABCB1. The ABCB1-dependent ATPase activity stimulated by nitensidine A was greatly reduced by substituting sulfur (S) or oxygen (O) for the imino nitrogen atom (N) in nitensidine A. Molecular docking studies on human ABCB1 showed that, guanidine alkaloids from P. nitens dock to the same binding pocket as verapamil. Nitensidine A and its analogs exhibit similar binding energies to verapamil. Taken together, this research clearly indicates that nitensidine A is a novel substrate for ABCB1. The present results also suggest that the number, binding site, and polymerization degree of the isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their stimulation of ABCB1's ATPase activity. |
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| Keywords: | ATP-binding cassette (ABC) transporter ABCB1 P-glycoprotein Guanidine alkaloid |
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