Biochemical and Biophysical Research Communications
Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase
Section snippets
Materials and methods
Chemicals. Zoledronate was purchased from Novartis (Basel, Switzerland). Digeranyl bisphosphonate (Fig. 1c) was synthesized as described previously [18]. Lovastatin and isoprenoid pyrophosphates were obtained from Sigma–Aldrich (St. Louis, MO).
Cell culture. Human-derived RPMI-8226 myeloma cells were obtained from ATCC (Manasas, VA) and cultured according to manufacturer’s protocol. Suspension cultures (1 × 106 cells/ml) were incubated for 24 h with the indicated compound concentrations. Western
Results and discussion
In recent years, many studies have identified FPP synthase as the molecular target of bisphosphonates while implicating GGPP as the most important depleted isoprenoid. However, few attempts have been made at development of GGPP synthase inhibitors, and the most potent bisphosphonate inhibitor of GGPP synthase described to date is the saturated 1-hydroxydecane-1,1-bisphosphonate, which has a reported in vitro IC50 of approximately 700 nM [17]. We have recently described the synthesis of a novel
Acknowledgments
This project was supported in part by the Roy. J. Carver Charitable Trust as a Research Program of Excellence, the Roland W. Holden Family Program for Experimental Cancer Therapeutics, the lowa Center on Aging, and the Iowa Centers for Enterprise. We thank the laboratory of Dr. David F. Wiemer for synthesis of digeranyl bisphosphonate.
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