Molecular Mechanisms of Action of Bisphosphonates: Current Status
Open Access
- 15 October 2006
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 12 (20), 6222s-6230s
- https://doi.org/10.1158/1078-0432.ccr-06-0843
Abstract
Purpose: Bisphosphonates are currently the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia. These compounds have high affinity for calcium ions and therefore target bone mineral, where they are internalized by bone-resorbing osteoclasts and inhibit osteoclast function. Experimental Design: This article reviews the pharmacology of bisphosphonates and the relationship between chemical structure and antiresorptive potency. We also describe new insights into their intracellular molecular mechanisms of action, methods for assessing the effects of bisphosphonates on protein prenylation, and their potential as direct antitumor agents. Results: Nitrogen-containing bisphosphonates act intracellularly by inhibiting farnesyl diphosphate synthase, an enzyme of the mevalonate pathway, thereby preventing prenylation of small GTPase signaling proteins required for normal cellular function. Inhibition of farnesyl diphosphate synthase also seems to account for their antitumor effects observed in vitro and for the activation of γ,δ T cells, a feature of the acute-phase response to bisphosphonate treatment in humans. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that seems to involve primarily the formation of cytotoxic metabolites in osteoclasts. Conclusions: Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts in vivo but could also have direct effects on other cell types, such as tumor cells. After >30 years of clinical use, their molecular mechanisms of action on osteoclasts are finally becoming clear but their exact antitumor properties remain to be clarified.Keywords
This publication has 71 references indexed in Scilit:
- The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugsProceedings of the National Academy of Sciences of the United States of America, 2006
- Zoledronic Acid (Zometa®) Enhances the Cytotoxic Effect of Gemcitabine and Fluvastatin: In vitro Isobologram Studies with Conventional and Nonconventional Cytotoxic AgentsOncology, 2006
- HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibitionBlood, 2005
- Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell linesLung Cancer, 2005
- Zoledronic Acid Inhibits Visceral Metastases in the 4T1/luc Mouse Breast Cancer ModelClinical Cancer Research, 2004
- The Ability of Statins to Inhibit Bone Resorption Is Directly Related to Their Inhibitory Effect on HMG-CoA Reductase ActivityJournal of Bone and Mineral Research, 2003
- γδ Cells: A Right Time and a Right Place for a Conserved Third Way of ProtectionAnnual Review of Immunology, 2000
- Nitrogen-Containing Bisphosphonates as Carbocation Transition State Analogs for Isoprenoid BiosynthesisBiochemical and Biophysical Research Communications, 1999
- Farnesyl Pyrophosphate Synthase Is the Molecular Target of Nitrogen-Containing BisphosphonatesBiochemical and Biophysical Research Communications, 1999
- Regulation of the mevalonate pathwayNature, 1990