Alendronate Is a Specific, Nanomolar Inhibitor of Farnesyl Diphosphate Synthase

Bergstrom, James D.; Bostedor, Richard G.; Masarachia, P.; Reszka, Alfred A.; Rodan, Gideon A.

doi:10.1006/abbi.1999.1502

Cited by 362 publications

(290 citation statements)

References 30 publications

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“…Nitrogen-containing bisphosphonates (N-BP) such as alendronate have been shown to act by inhibiting the mevalonate pathway, thereby preventing prenylation of small GTPase signaling proteins such as RhoA. This mechanism of action has been demonstrated to be operative in osteoclasts (Bergstrom, 2000) and in osteoblasts (Idris et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Morphological changes induced by advanced glycation endproducts in osteoblastic cells: Effects of co-incubation with alendronate

et al. 2013

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a b s t r a c tAdvanced glycation endproducts (AGEs) accumulate with age in various tissues, and are further increased in patients with Diabetes mellitus, in which they are believed to contribute to the development and progression of chronic complications that include a decrease in bone quality. Bisphosphonates are antiosteoporotic drugs that have been used for the treatment of patients with diabetic bone alterations, although with contradictory results. In the present study, we have evaluated the in vitro alterations on osteoblastic morphology by environmental scanning electron microscopy, in actin cytoskeleton and apoptosis induced by AGEs, as well as the modulation of these effects by alendronate (an N-containing bisphosphonate). Our present results provide evidence for disruption induced by AGEs of the osteoblastic actin cytoskeleton (geodesic domes) and significant alterations in cell morphology with a decrease in cellsubstratum interactions leading to an increase in apoptosis of osteoblasts and a decrease in osteoblastic proliferation. High concentrations of alendronate (10 −5 M, such as could be expected in an osteoclastic lacuna) further increase osteoblastic morphological and cytoskeletal alterations. However, low doses of alendronate (10 −8 M, compatible with extracellular fluid levels to which an osteoblast could be exposed for most of its life cycle) do not affect cell morphology, and in addition are able to prevent AGEs-induced alterations and consequently apoptosis of osteoblasts.

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Section: Discussionmentioning

confidence: 99%

Morphological changes induced by advanced glycation endproducts in osteoblastic cells: Effects of co-incubation with alendronate

et al. 2013

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“…The N-BPs act by inhibiting FPP synthase, 18,19 an enzyme of the mevalonate pathway, leading to inhibition of protein prenylation. 20 In accordance with this, RIS dose-dependently caused an accumulation of unprenylated Rap1A (geranylgeranylated by GGTase I) and Rab6 (geranylgeranylated by Rab GGTase) proteins in the myeloma cells, which could be blocked by GGOH.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17] N-BPs, such as RIS, act on the mevalonate pathway by specifically inhibiting the enzyme farnesyl diphosphate (FPP) synthase. 18,19 This leads to inhibition of prenylation of target proteins, which mainly include small GTPases such as Ras, Rho, Rac and Rab. 20 Protein prenylation is essential for membrane anchorage and correct protein-protein interactions.…”

mentioning

confidence: 99%

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

Roelofs¹,

Hulley²,

Meijer³

et al. 2006

Intl Journal of Cancer

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Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen‐containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3‐PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3‐PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3‐PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose‐dependently inhibited prenylation of both Rap1A and Rab6, whereas 3‐PEHPC only inhibited Rab6 prenylation. Both RIS and 3‐PEHPC dose‐dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S‐phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3‐PEHPC did not cause cell‐cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell‐cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3‐PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3‐PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S‐phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen‐containing BPs. © 2006 Wiley‐Liss, Inc.

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“…The first generation consists in non-nitrogen-containing BPs that are metabolised in nonhydrolysable ATP analogues, whereas the more recent generations, including zoledronic acid (ZOL), are nitrogen-containing BPs (N-BPs). One possible mechanism by which N-BPs mediate their effects is based on their ability to inhibit some of the enzymes involved in the mevalonate (MVA) pathway, such as farnesylpyrophosphate synthase (van Beek et al, 1999;Bergstrom et al, 2000) and/or geranylgeranylpyrophosphate synthase (Coxon et al, 2000), thus blocking the generation of isoprenoid compounds, farnesyl pyrophosphate (FPP) and/ or geranylgeranyl pyrophosphate (GGPP), respectively. These intermediates are required for post-translational prenylation (farnesylation and geranylgeranylation) of key regulatory proteins, a step that is needed to their attachment to the plasma membrane, where they are fully active and can exert their biological function (Sinensky, 2000).…”

mentioning

confidence: 99%

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Denoyelle¹,

Li²,

Jp³

et al. 2003

Br J Cancer

147

110

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Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 mM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoAindependent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclastmediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.

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Alendronate Is a Specific, Nanomolar Inhibitor of Farnesyl Diphosphate Synthase

Cited by 362 publications

References 30 publications

Morphological changes induced by advanced glycation endproducts in osteoblastic cells: Effects of co-incubation with alendronate

Morphological changes induced by advanced glycation endproducts in osteoblastic cells: Effects of co-incubation with alendronate

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

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