Cell lines

breast cancer cell line (MDA-MB-231 and MCF-7 )

Preparation Method

The biological effects of various concentrations of NPS-2143 on breast cancer cell proliferation measured by in vitro MTT assay.

Reaction Conditions

0.5-10 μM NPS-2143 for 48 h.

Applications

The cell viability of both MDA-MB-231 and MCF-7 cells was reduced after NPS-2143 treatment in a dose-dependent manner. 5-10 μM NPS-2143 significantly reduced MCF-7 and MDA-MB-23 cell viability as compared to DMSO-treated controls.

Animal models

wild-type, Nuf/+, and Nuf/Nuf mice

Preparation Method

A single bolus of NPS 2143 or vehicle (15% aqueous solution of 2-hydroxypropyl- β-cyclodextrin) was administered to mice. Plasma samples were obtained at either 0, 1, 4, or 24 hours by tail vein or terminal bleed.

Dosage form

30 mg/kg, i.p. injection

Applications

NPS-2143 successfully improved the hypocalcemia associated with Nuf/+ and Nuf/Nuf mice compared with mice given the drug vehicle alone or untreated mice. At 4 hours after NPS 2143 administration, plasma calcium values remained significantly elevated in wild-type and affected Nuf/+ mice compared with respective untreated mice.

NPS-2143 is a calcification drug that acts as an antagonist of the calcium-sensing receptor (CaSR) and consequently stimulates the release of parathyroid hormone^[1].

Treating Cortical nontumorigenic adult human astrocytes(NAHAs) with fAβ25–35 alone significantly increased at 48 h the release of cytokines and chemokines into the conditioned media. However, NPS-2143(100nM) effectively hinders the Secretion of cytokines and chemokines: IL-6, MCP-2, RANTES, and s-ICAM-1 from NAHAs^[2].

NPS-2143 significantly reduced cell proliferation with halfmaximal (50%) inhibitory concentration (IC50) values of 4.08 and 5.71 μM in MDA-MB-231 and MCF-7 cells, respectively. NPS-2143 induced caspase 3/7 activation in MDA-MB-231 breastcancer cells which was accompanied with a remarkable reduction in the expression of Bcl-2antiapoptotic protein. NPS-2143 suppressed migratory and invasive abilities of MDA-MB-231cells with a significant reduction in the expression of p-ERK1/2 and integrin β1 proteins.NPS-2143 to suppress proliferative, migratory andinvasive effects of breast cancer cells which was accompanied by caspase 3/7 activation andsuggests the potential of NPS-2143 as a promising anti-cancer molecule in breast cancer^[3].

NPS-2143 was administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS-2143 rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS-2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS-2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder^[4].

References:
[1].Wang S, Qiu L, et al. NPS - 2143 (hydrochloride) inhibits melanoma cancer cell proliferation and induces autophagy and apoptosis. Med Sci (Paris). 2018 Oct;34 Focus issue F1:87-93.
[2].Chiarini A, Armato U, et al. CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes. Cells. 2020 Jun 2;9(6):1386.
[3].Alqudah MAY, Azaizeh M, et al. Calcium-Sensing Receptor Antagonist NPS-2143 Inhibits Breast Cancer cell Proliferation, Migration and Invasion via Downregulation of p-ERK1/2, Bcl-2 and Integrin β1 and Induces Caspase 3/7 Activation. Adv Pharm Bull. 2022 Mar;12(2):383-388.
[4].Hannan FM, Walls GV, et al. The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). Endocrinology. 2015 Sep;156(9):3114-21.