Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis of Lymphocytic Leukemia Cells

Abstract

Bisphosphonates are metabolically stable diphosphate analogs that inhibit downstream enzymes in the mevalonate pathway and induce cell death. Here, we compared the effects of a farnesyl diphosphate synthase inhibitor, zoledronate, and a geranylgeranyl diphosphate synthase inhibitor, digeranyl bisphosphonate (DGBP), on lymphocytic leukemia cell proliferation and apoptosis. Both zoledronate and DGBP prevented Molt‐4 cell proliferation with DGBP doing so more potently. Surprisingly, DGBP was markedly less toxic than zoledronate towards the viability of healthy human peripheral blood mononuclear cells. Furthermore, addition of geranylgeranyl diphosphate rescued the inhibitory effects of DGBP and partially rescued the effects of zoledronate. In order to further assess the growth inhibitory effects of the bisphosphonates, we analyzed annexin V and PI staining via flow cytometry and found that DGBP was more potent than zoledronate in inducing apoptosis. We demonstrate via Western blot analysis that incubation with DGBP causes cleavage of caspase 3/7, increases ERK phosphorylation, and elevates RhoA protein levels. Taken together, our findings indicate that DGBP is a more potent and selective compound than zoledronate in inducing apoptosis mediated through RhoA, ERK and the caspase pathway. These findings support the further development of geranylgeranyl diphosphate synthase inhibitors as anti‐cancer therapeutics.