Inhibition of geranylgeranyl diphosphate synthase induces apoptosis through multiple mechanisms and displays synergy with inhibition of other isoprenoid biosynthetic enzymes

Amel Dudakovic, Andrew J. Wiemer, Kimberly M. Lamb, Laura A. Vonnahme, Sara E. Dietz, Raymond J. Hohl

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Inhibitors of isoprenoid synthesis are widely used for treatment of human diseases, including hypercholesterolemia and osteoporosis, and they have the potential to be useful for treatment of cancer. Statin drugs inhibit the enzyme HMG-CoA reductase, whereas nitrogenous bisphosphonates have more recently been shown to inhibit farnesyl disphosphate synthase. In addition, our laboratory has recently developed several potent and specific bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, including digeranyl bisphosphonate. Because all three enzymes fall in the same biosynthetic pathway and many of the biological effects are due to depletion of downstream products, we hypothesized that simultaneous inhibition of these enzymes would result in synergistic growth inhibition. In this study, we show that inhibition of geranylgeranyl diphosphate synthase induces apoptosis in K562 leukemia cells. This induction of apoptosis is in part dependent upon both geranylgeranyl diphosphate depletion and accumulation of farnesyl diphosphate. Combinations of either lovastatin or zoledronate with digeranyl bisphosphonate synergistically inhibited growth and induced apoptosis. These combinations also potently inhibited cellular geranylgeranylation. These results support the potential for combinations of multiple inhibitors of isoprene biosynthesis to inhibit cancer cell growth or metastasis at clinically achievable concentrations.

Original languageEnglish (US)
Pages (from-to)1028-1036
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number3
DOIs
StatePublished - Mar 1 2008

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Farnesyltranstransferase
Terpenes
zoledronic acid
Diphosphonates
Apoptosis
Enzymes
Growth
Prenylation
Hydroxymethylglutaryl CoA Reductases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lovastatin
K562 Cells
Biosynthetic Pathways
Hypercholesterolemia
Osteoporosis
Neoplasms
Leukemia
Neoplasm Metastasis
Pharmaceutical Preparations
digeranyl bisphosphonate

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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abstract = "Inhibitors of isoprenoid synthesis are widely used for treatment of human diseases, including hypercholesterolemia and osteoporosis, and they have the potential to be useful for treatment of cancer. Statin drugs inhibit the enzyme HMG-CoA reductase, whereas nitrogenous bisphosphonates have more recently been shown to inhibit farnesyl disphosphate synthase. In addition, our laboratory has recently developed several potent and specific bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, including digeranyl bisphosphonate. Because all three enzymes fall in the same biosynthetic pathway and many of the biological effects are due to depletion of downstream products, we hypothesized that simultaneous inhibition of these enzymes would result in synergistic growth inhibition. In this study, we show that inhibition of geranylgeranyl diphosphate synthase induces apoptosis in K562 leukemia cells. This induction of apoptosis is in part dependent upon both geranylgeranyl diphosphate depletion and accumulation of farnesyl diphosphate. Combinations of either lovastatin or zoledronate with digeranyl bisphosphonate synergistically inhibited growth and induced apoptosis. These combinations also potently inhibited cellular geranylgeranylation. These results support the potential for combinations of multiple inhibitors of isoprene biosynthesis to inhibit cancer cell growth or metastasis at clinically achievable concentrations.",
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Inhibition of geranylgeranyl diphosphate synthase induces apoptosis through multiple mechanisms and displays synergy with inhibition of other isoprenoid biosynthetic enzymes. / Dudakovic, Amel; Wiemer, Andrew J.; Lamb, Kimberly M.; Vonnahme, Laura A.; Dietz, Sara E.; Hohl, Raymond J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 3, 01.03.2008, p. 1028-1036.

Research output: Contribution to journalArticle

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