The mevalonate pathway produces isoprenoids including geranylgeranyl diphosphate (GGPP), the lipid moiety of which attaches to some small GTPases in a post-translational modification that allows the proteins to associate with membranes. Bisphosphonates such as zoledronate are known inhibitors of the mevalonate pathway. We have previously developed a library of novel bisphosphonates, including digeranyl bisphosphonate (DGBP), which inhibit geranylgeranyl diphosphate synthase (GGDPS) and thus deplete GGPP [1]. Here, we compare the effects of zoledronate and DGBP on lymphocytic leukemia cell apoptosis through annexin V and propidium iodide staining and through western blot analysis of cleaved caspase 3 and 7 levels. To investigate the cellular mechanisms involved in inducing apoptosis, we determined that DGBP and zoledronate induce ERK phosphorylation and that DGBP differentially alters expression and localization of RhoA GTPase. Overall, DGBP selectively and potently induces apoptosis and may be a promising leukemia therapeutic. Reference: 1. Wiemer, A.J., D.F. Wiemer, and R.J. Hohl, Geranylgeranyl Diphosphate Synthase: An Emerging Therapeutic Target. Clinical Pharmacology & Therapeutics, 2011. 90(6): p. 804-812.

Inhibition of geranylgeranyl diphosphate synthase mediates selective apoptosis through a RhoA/ERK pathway

250th National Meeting (2015)

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