Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake

Michael John Rogers, X Xiong, X Ji, J Mönkkönen, R G Russell, M P Williamson, F H Ebetino, D J Watts

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Abstract

PURPOSE: The aim of the study was to determine whether bisphosphonates are internalised by Dictyostelium amoebae 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 31P-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.
Original languageEnglish
Pages (from-to)625-30
Number of pages6
JournalPharmaceutical Research
Volume14
Issue number5
Publication statusPublished - 1 May 1997

Keywords

  • Adenine Nucleotides
  • Animals
  • Antifungal Agents
  • Chromatography, Ion Exchange
  • Dictyostelium
  • Diphosphonates
  • Drug Carriers
  • Drug Compounding
  • Liposomes
  • Magnetic Resonance Spectroscopy

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    Rogers, M. J., Xiong, X., Ji, X., Mönkkönen, J., Russell, R. G., Williamson, M. P., Ebetino, F. H., & Watts, D. J. (1997). Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake. Pharmaceutical Research, 14(5), 625-30.