Received for publication October 2, 2007.
Revised November 20, 2007.
Accepted for publication December 13, 2007.

Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of other Isoprenoid Biosynthetic Enzymes

Abstract

Inhibitors of isoprenoid synthesis are widely used for treatment of human diseases including hypercholesterolemia and osteoporosis and have the potential to be useful for treatment of cancers. Statin drugs inhibit the enzyme HMG-CoA reductase while nitrogenous bisphosphonates have more recently been shown to inhibit farnesyl disphosphate synthase. Additionally, our lab has recently developed a number of 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. Here we show that inhibition of geranylgeranyl diphosphate synthase induces apoptosis in K562 leukemia cells. This induction of apoptosis is in part dependant 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.

Key words: bisphosphonate, digeranyl bisphosphonate, farnesol, geranylgeranyl diphosphate synthase, geranylgeranylation, mevalonate