Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of Other Isoprenoid Biosynthetic Enzymes
| Autor: | Amel Dudakovic, Andrew J. Wiemer, Sara E. Dietz, Kimberly M. Lamb, Laura A. Vonnahme, Raymond J. Hohl |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_treatment
Apoptosis Pharmacology chemistry.chemical_compound Geranylgeranylation Biosynthesis medicine Farnesyltranstransferase Humans Enzyme Inhibitors chemistry.chemical_classification ATP synthase biology Terpenes Bisphosphonate Enzyme chemistry Biochemistry Cancer cell biology.protein Molecular Medicine Lovastatin Growth inhibition K562 Cells medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 324:1028-1036 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.107.132217 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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