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

Research output: Contribution to journalArticle

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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

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Amoeba
Dictyostelium
Diphosphonates
Growth
Pharmaceutical Preparations
Pinocytosis
Cell Extracts
Growth Inhibitors
Fluids
Ion Exchange
Osteoclasts
Bone Resorption
Metabolites
Liposomes
Spectrum Analysis
Ion exchange
Bone
Fungi

Keywords

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

Cite this

Rogers, M. J., Xiong, X., Ji, X., Mönkkönen, J., Russell, R. G., Williamson, M. P., ... 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.

Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake. / Rogers, Michael John; Xiong, X; Ji, X; Mönkkönen, J; Russell, R G; Williamson, M P; Ebetino, F H; Watts, D J.

In: Pharmaceutical Research, Vol. 14, No. 5, 01.05.1997, p. 625-30.

Research output: Contribution to journalArticle

Rogers, MJ, Xiong, X, Ji, X, Mönkkönen, J, Russell, RG, Williamson, MP, Ebetino, FH & Watts, DJ 1997, 'Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake', Pharmaceutical Research, vol. 14, no. 5, pp. 625-30.
Rogers MJ, Xiong X, Ji X, Mönkkönen J, Russell RG, Williamson MP et al. Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake. Pharmaceutical Research. 1997 May 1;14(5):625-30.
Rogers, Michael John ; Xiong, X ; Ji, X ; Mönkkönen, J ; Russell, R G ; Williamson, M P ; Ebetino, F H ; Watts, D J. / Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake. In: Pharmaceutical Research. 1997 ; Vol. 14, No. 5. pp. 625-30.
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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.",
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T1 - Inhibition of growth of Dictyostelium discoideum amoebae by bisphosphonate drugs is dependent on cellular uptake

AU - Rogers, Michael John

AU - Xiong, X

AU - Ji, X

AU - Mönkkönen, J

AU - Russell, R G

AU - Williamson, M P

AU - Ebetino, F H

AU - Watts, D J

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N2 - 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.

AB - 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.

KW - Adenine Nucleotides

KW - Animals

KW - Antifungal Agents

KW - Chromatography, Ion Exchange

KW - Dictyostelium

KW - Diphosphonates

KW - Drug Carriers

KW - Drug Compounding

KW - Liposomes

KW - Magnetic Resonance Spectroscopy

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VL - 14

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EP - 630

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

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ER -