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 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.

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

“…This compound specifically impairs protein geranylgeranylation via depletion of GGPP in various cell types. Furthermore, GGPP depletion results in the inhibition of cancer cell migration (Dudakovic et al, 2010) and induction of apoptosis (Dudakovic et al, 2008). We hypothesize and provide evidence herein to support that depletion of GGPP by bisphosphonate inhibitors of FDPS (i.e., zoledronate) or GGDPS (i.e., DGBP) results in the induction of autophagy.…”

“…Many of the cellular effects of these agents have been attributed to the depletion of GGPP (Xia et al, 2001;Coxon et al, 2004). Our prior work further explored cellular consequences of GGPP depletion through the utilization of a novel bisphosphonate that directly inhibits GGDPS (Dudakovic et al, 2008(Dudakovic et al, , 2010. Other recent work has suggested that statins can induce autophagy (Parikh et al, 2010).…”

Physiologic Activity of Bisphosphonates – Recent Advances

“…A recent report on the use of lovastatin, zoledronate and digeranylbisphosphonate (Scheme 7) indicated that the simultaneous use of these three compounds as inhibitors of three subsequent steps in geranylgeranyl synthesis led to the inhibition of growth and induction of apoptosis in human chronic myelogenous leukemia cells [142,143]. Scheme (7).…”

Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration

“…Our lead compound, digeranyl bisphosphonate (DGBP), has been shown to specifically inhibits GGDPS and disrupt proteins geranylgeranylation [28]. GGDPS inhibition depleted GGPP while it increased FPP levels in cultured cells and some mammalian tissues [31,32].…”