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.
Footnotes
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This work was supported by the Roy J. Carver Charitable Trust as a Research Program of Excellence, the Roland W. Holden Family Program for Experimental Cancer Therapeutics, and the Iowa Center for Research by Undergraduates.
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A.D. and A.J.W. contributed equally to this article.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132217.
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ABBREVIATIONS: HMGCR, HMG-CoA reductase; FPP, farnesyl diphosphate; GGPP, geranylgeranyl diphosphate; NBP, nitrogenous bisphosphonate; FDPS, farnesyl diphosphate synthase; GGDPS, geranylgeranyl diphosphate synthase; DGBP, digeranyl bisphosphonate; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; PI, propidium iodide; PCR, polymerase chain reaction; PARP, poly(ADP-ribose) polymerase; RT, room temperature; PBS, phosphate-buffered saline; CI, combination index; GGOH, geranylgeraniol; GGTase, geranylgeranyl transferase; FOH, farnesol; PC, phosphatidylcholine; SQS, squalene synthase; Lov, lovastatin; GGTI-298, N-4-[2(R)-amino-3-mercaptopropyl]amino-2-naphthylbenzoyl-(l)-leucine methyl ester trifluoroacetate.
- Received September 27, 2007.
- Accepted December 13, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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