Bisphosphonates: Future perspective for neurological disorders

Zameer, Saima; Najmi, Abul Kalam; Vohora, Divya; Akhtar, Mohd

doi:10.1016/j.pharep.2018.03.011

Cited by 39 publications

(27 citation statements)

References 91 publications

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“…Since then, the BPs have evolved to become one of the most successful and widely used groups of drugs in the world, dramatically improving the treatment of Paget's disease of bone, osteoporosis, metastatic bone disease, multiple myeloma and several rare bone diseases . BPs are currently also being explored for use in various other disease areas, including non‐skeletal applications such as neurodegenerative diseases . There is also a renewed interest in using the bisphosphonates as bone‐targeting carriers for other drugs such as antibiotics, hormones and anti‐cancer drugs …”

Section: Introductionmentioning

confidence: 99%

Pharmacology of bisphosphonates

Cremers

Drake

Ebetino

et al. 2019

Brit J Clinical Pharma

173

107

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The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from "bench to bedside and back again". Several of the leading BPs achieved "blockbuster" status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.

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Section: Introductionmentioning

confidence: 99%

Pharmacology of bisphosphonates

Cremers

Drake

Ebetino

et al. 2019

Brit J Clinical Pharma

173

107

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“…We excluded a toxic effect of the drug through a dose-dependence cell-survival curve (data not shown). ZA is a specific inhibitor of farnesyl pyrophosphate (FPP) synthase in the mevalonate pathway, which produces isoprenoids and cholesterol [10]. Isoprenoids are required for post-translation prenylation of several regulatory proteins, and also for the geranyl-geranylation of RhoA [30].…”

Section: Za Inhibits Invasion Of Pc3 Cells and Rhoa Activitymentioning

confidence: 99%

“…ZA is a specific inhibitor of farnesyl pyrophosphate (FPP) synthase, an enzyme involved in the mevalonate pathway, which produces isoprenoids and cholesterol [10]. Isoprenoid compounds, such as FPP and/or geranylgeranyl pyrophosphate are required for post-translation prenylation of several regulatory proteins.…”

Section: Introductionmentioning

confidence: 99%

Zoledronic Acid Inhibits the RhoA-mediated Amoeboid Motility of Prostate Cancer Cells

Pietrovito

Comito

Parri

et al. 2019

CCDT

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Background: The bisphosphonate Zoledronic acid (ZA) is a potent osteoclast inhibitor currently used in the clinic to reduce osteoporosis and cancer-induced osteolysis. Moreover, ZA exerts an anti-tumor effect in several tumors. Despite this evidence, the relevance of ZA in prostate cancer (PCa) is not completely understood. Objective: To investigate the effect of ZA administration on the invasive properties of PC3 cells, which are characterised by RhoA-dependent amoeboid motility. Methods: The effect of ZA administration on the in vitro invasive properties of PC3 cells was evaluated by cell migration in 3D collagen matrices, immunofluorescence and Boyden assays or transendothelial migration. Lung retention and colonization assays were performed to assess the efficacy of ZA administration in vivo. Results: PC3 cells are characterised by RhoA-dependent amoeboid motility. We now report a clear inhibition of in vitro PC3 cell invasion and RhoA activity upon ZA treatment. Moreover, to confirm a specific role of ZA in the inhibition of amoeboid motility of PC3 cells, we demonstrate that ZA interferes only partially with PC3 cells showing a mesenchymal phenotype due to both treatment with conditioned medium of cancer associated fibroblasts or to the acquisition of chemoresistance. Furthermore, we demonstrate that ZA impairs adhesion to endothelial cells and the trans-endothelial cell migration, two essential properties characterising amoeboid motility and PC3 metastatic dissemination. In vivo experiments prove the ability of ZA to inhibit the metastatic process of PC3 cells as shown by the decrease in lung colonization. Conclusion: This study demonstrates that ZA inhibits Rho-dependent amoeboid motility of PC3 cells, thus suggesting ZA as a potential therapy to impede the metastatic dissemination of PC3 cells.

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“…[23] The potential use of bisphosphonates for other indications is a subject of intense investigations. [27][28][29][30][31] FPPS is considered a highly interesting potential target also for the treatment of malaria, Chagas disease, Leishmaniasis and HAT caused by Plasmodium vivax, Trypanosoma cruzi, Leishmania mexicana and T. brucei, respectively. [27] An IC 50 of 220 nM for ortho-risedronate on the bloodstream form of T. brucei was first described in an in vitro growth inhibition assay as part of a study on various parasitic organisms.…”

Section: Introductionmentioning

confidence: 99%

Fragment‐Based Discovery of Non‐bisphosphonate Binders of Trypanosoma brucei Farnesyl Pyrophosphate Synthase

et al. 2020

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Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). Nitrogen-containing bisphosphonates, a current treatment for bone diseases, have been shown to block the growth of the T. brucei parasites by inhibiting farnesyl pyrophosphate synthase (FPPS); however, due to their poor pharmacokinetic properties, they are not well suited for antiparasitic therapy. Recently, an allosteric binding pocket was discovered on human FPPS, but its existence on trypanosomal FPPS was unclear. We applied NMR and X-ray fragment screening to T. brucei FPPS and report herein on four fragments bound to this previously unknown allosteric site. Surprisingly, nonbisphosphonate active-site binders were also identified. Moreover , fragment screening revealed a number of additional binding sites. In an early structure-activity relationship (SAR) study, an analogue of an active-site binder was unexpectedly shown to bind to the allosteric site. Overlaying identified fragment binders of a parallel T. cruzi FPPS fragment screen with the T. brucei FPPS structure, and medicinal chemistry optimisation based on two binders revealed another example of fragment "pocket hopping". The discovery of binders with new chemotypes sets the framework for developing advanced compounds with pharmacokinetic properties suitable for the treatment of parasitic infections by inhibition of FPPS in T. brucei parasites.

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Bisphosphonates: Future perspective for neurological disorders

Cited by 39 publications

References 91 publications

Pharmacology of bisphosphonates

Pharmacology of bisphosphonates

Zoledronic Acid Inhibits the RhoA-mediated Amoeboid Motility of Prostate Cancer Cells

Fragment‐Based Discovery of Non‐bisphosphonate Binders of Trypanosoma brucei Farnesyl Pyrophosphate Synthase

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