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

Pharm Res. 1997 May;14(5):625-30. doi: 10.1023/a:1012157212793.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotides / metabolism
  • Animals
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology*
  • Chromatography, Ion Exchange
  • Dictyostelium / drug effects
  • Dictyostelium / growth & development*
  • Dictyostelium / metabolism
  • Diphosphonates / administration & dosage
  • Diphosphonates / metabolism
  • Diphosphonates / pharmacology*
  • Drug Carriers
  • Drug Compounding
  • Liposomes
  • Magnetic Resonance Spectroscopy


  • Adenine Nucleotides
  • Antifungal Agents
  • Diphosphonates
  • Drug Carriers
  • Liposomes