Inhibition of Growth of Dictyostelium discoideum Amoebae by Bisphosphonate Drugs Is Dependent on Cellular Uptake |
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Authors: | Rogers Michael J Xiong Xiaojuan Ji Xiaohui Mönkkönen Jukka Russell R Graham G Williamson Michael P Ebetino Frank H Watts Donald J |
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Institution: | (1) Institute for Bone and Joint Medicine, Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, UK;(2) Department of Molecular Biology and Biotechnology, University of Sheffield, Krebs Institute, PO Box 594, Firth Court, Western Bank, Sheffield, S10 2UH, UK;(3) Department of Pharmaceutics, University of Kuopio, Finland;(4) Institute for Bone and Joint Medicine, Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, UK;(5) Procter & Gamble Pharmaceuticals, Cincinnati, Ohio |
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Abstract: | Purpose. The aim of the study was to determine whether bisphosphonates are internalised by Dictyosteliumamoebae and whether cellular uptake is required for their growth-inhibitory effects. Bisphosphonates inhibit growth of amoebae of the slime mould Dictyostelium discoideum, by mechanisms that appear to be similar to those that cause inhibition of osteoclastic bone resorption.
Methods. Cell-free extracts prepared from amoebae that had been incubated with bisphosphonates were analysed by 3lP-n.m.r. spectroscopy or ion-exchange f.p.l.c., to identify the presence of bisphosphonates or bisphosphonate metabolites respectively. The growth-inhibitory effect of bisphosphonates towards Dictyostelium amoebae was also examined under conditions in which pinocytosis was inhibited.
Results. All of the bisphosphonates studied were internalised by Dictyostelium amoebae, probably by fluid-phase pinocytosis, and could be detected in cell-free extracts. Amoebae that were prevented from internalising bisphosphonates by pinocytosis were markedly resistant to the growth-inhibitory effects of these compounds. In addition, bisphosphonates encapsulated within liposomes were more potent growth inhibitors of Dictyostelium owing to enhanced intracellular delivery of bisphosphonates.
Conclusions. All bisphosphonates inhibit Dictyostelium growth by intracellular mechanisms following internalisation of bisphosphonates by fluid-phase pinocytosis. It is therefore likely that bisphosphonates also affect osteoclasts by interacting with intracellular, rather than extracellular, processes. |
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Keywords: | bisphosphonates Dictyostelium endocytosis growth inhibition 31P-n m r osteoclasts |
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