Zoledronic acid monohydrate

Catalog No.S5244 Batch:S524401

Technical Data

Formula	C₅H₁₀N₂O₇P₂.H₂O
Molecular Weight	290.1	CAS No.	165800-06-6
Solubility (25°C)*	In vitro	0.5MNAOH	6.02 mg/mL (20.75 mM)
		Water	2.3 mg/mL (7.92 mM)
		DMSO	0.01 mg/mL (0.03 mM)
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

Zoledronic acid (Zoledronate, CGP-4244) monohydrate, a nitrogen-containing bisphosphonate, is a potent osteoclast inhibitor which induces apoptosis in osteoclasts by inhibiting enzymes of the mevalonate pathway and preventing the isoprenylation of small GTP-binding proteins such as Ras and Rho.

Targets

Ras ^[1]

Rho ^[1]

In vitro

Zoledronic acid inhibits osteoclast maturation indirectly by increasing OPG protein secretion and decreasing transmembrane RANKL expression in human osteoblasts. Treatment of primary human OB‐like cells with the potent nitrogen-containing BP, zoledronic acid (ZOL), resulted in a downregulation of membrane-ssociated RANKL protein expression. In addition to direct effects on cells of the osteoclast lineage, zoledronic acid may inhibit bone resorption by reducing transmembrane RANKL expression and increasing OPG secretion in osteoclast (OB)-like cells^[1]. Zoledronic acid induces growth inhibition (IC50:10–50 μM) and apoptotic death of human pancreatic cancer cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. It interferes with growth and survival pathways downstream to p21^ras^[2]. Zoledronic acid is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC50 values 4.1, 4.2, and 6.9 μM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. ZOL also exerted a concentration-dependent, biphasic effect on the adhesion and migration of HUVEC in vitro. ZOL concentrations of 1 and 3 μM increased cell adhesion but inhibited it at 30 and 100 μM. Similarly, cell migration was stimulated by 0.3 to 10 μM ZOL, whereas 30 μM completely inhibited it. These findings suggest that ZOL could interfere with cytoskeletal function in endothelial cells^[4].

In vivo

Zoledronic acid affects breast cancer metastasis to visceral organs as well as bone^[3]. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED50, 3 μg/kg (7.5 nmol/kg) s.c.]^[4]. In nice transplanted with osteosarcoma (OS) cells, ZOL administration prevented osteolysis and significantly reduced the amount of OS-induced bone formation while has no effect on tumor burden at the primary site. ZOL failed to reduce lung metastasis and in some cases was associated with larger and more numerous metastatic lesions^[5].

Protocol (from reference)

Cell Assay:^{^[2]}	Cell lines human PC cell lines (BxPC-3, CFPAC-1 and PANC-1) Concentrations 1-100 μM Incubation Time 72 h Method 'BxPC-3 and CFPAC-1 are adherent human pancreatic adenocarcinoma cell lines that were grown in RPMI 1640 and Iscove's modified Dulbecco's media, respectively. PANC-1 is a human epithelioid pancreas carcinoma cell line that was grown in Dulbecco's modified Eagle's medium (DMEM). All media were supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 100 μg/ml streptomycin and 100 U/ml penicillin. All PC cell lines were cultured at a constant temperature of 37°C in a humidified atmosphere of 5% carbon dioxide (CO2). The neutralised sodium salt of ZOL was dissolved in sterile ddH2O and used at a final concentration in a range of 1-100 μM. Analysis of cell proliferation was performed on PC cells in the presence of increasing concentrations of ZOL by the MTT assay. Briefly, PC cells (3 × 10⁴/well) were seeded in 96-well plates in serum-containing media and allowed to attach for 24 h. The medium was then removed and replaced with new medium containing ZOL at different concentrations. Cells were incubated under these conditions for a time course spanning 72 h. Then cells were incubated with 10 μl well−1 of thiazolyl blue (MTT, 5 mg/ml) for 1 h at 37°C. After incubation, 100 μl of 0.04 N HCl in isopropanol was added into each well and the absorbance was measured at a wavelength of 620 nm in a microplate reader.
Animal Study:^{^[4]}	Animal Models Female mice (strain Tiflbm:MAG) Dosages 1, 10 and 100 μg/kg Administration s.c.

Cell Assay:^{^[2]}

Cell lines
human PC cell lines (BxPC-3, CFPAC-1 and PANC-1)
Concentrations
1-100 μM
Incubation Time
72 h
Method
'BxPC-3 and CFPAC-1 are adherent human pancreatic adenocarcinoma cell lines that were grown in RPMI 1640 and Iscove's modified Dulbecco's media, respectively. PANC-1 is a human epithelioid pancreas carcinoma cell line that was grown in Dulbecco's modified Eagle's medium (DMEM). All media were supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 100 μg/ml streptomycin and 100 U/ml penicillin. All PC cell lines were cultured at a constant temperature of 37°C in a humidified atmosphere of 5% carbon dioxide (CO2). The neutralised sodium salt of ZOL was dissolved in sterile ddH2O and used at a final concentration in a range of 1-100 μM. Analysis of cell proliferation was performed on PC cells in the presence of increasing concentrations of ZOL by the MTT assay. Briefly, PC cells (3 × 10⁴/well) were seeded in 96-well plates in serum-containing media and allowed to attach for 24 h. The medium was then removed and replaced with new medium containing ZOL at different concentrations. Cells were incubated under these conditions for a time course spanning 72 h. Then cells were incubated with 10 μl well−1 of thiazolyl blue (MTT, 5 mg/ml) for 1 h at 37°C. After incubation, 100 μl of 0.04 N HCl in isopropanol was added into each well and the absorbance was measured at a wavelength of 620 nm in a microplate reader.

Animal Study:^{^[4]}

Animal Models
Female mice (strain Tiflbm:MAG)
Dosages
1, 10 and 100 μg/kg
Administration
s.c.

References

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Selleck's Zoledronic acid monohydrate has been cited by 12 publications

Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab [ J Immunother Cancer, 2022, 10(12)e005660]	PubMed: 36543375
Estrogen Responsive Gene MAST4 Regulates Myeloma Bone Disease [ J Bone Miner Res, 2022, 10.1002/jbmr.4507]	PubMed: 35064934
CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia [ Oncol Lett, 2022, 23(2):51]	PubMed: 34992684
Establishment of a 3D model of tumor-driven angiogenesis to study the effects of anti-angiogenic drugs on pericyte recruitment [ Biomater Sci, 2021, 10.1039/d0bm02107e]	PubMed: 34136892
Classic and Targeted Anti-Leukaemic Agents Interfere With the Cholesterol Biogenesis Metagene in Acute Myeloid Leukaemia: Therapeutic Implications [ J Cell Mol Med, 2020, 25]	PubMed: 32450611
Nanoformulated Zoledronic Acid Boosts the Vδ2 T Cell Immunotherapeutic Potential in Colorectal Cancer. [ Cancers (Basel), 2020, 31;12(1) pii: E104]	PubMed: 31906080
Zoledronic acid re‑sensitises gefitinib‑resistant lung cancer cells by inhibiting the JAK/STAT3 signalling pathway and reversing epithelial‑mesenchymal transition [ Oncol Rep, 2020, 45(2):459-468]	PubMed: 33416163
The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells [ Immun Inflamm Dis, 2020, 10.1002/iid3.390]	PubMed: 33332777
The effects of mechanically loaded osteocytes and inflammation on bone remodeling in a bisphosphonate-induced environment [ Bone, 2019, 127:460-473]	PubMed: 31301402
A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells [ J Bone Miner Res, 2015, 30(8):1508-22]	PubMed: 25656537

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