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.
NPS-2143 是一种钙化药物，可作为钙敏感受体 (CaSR) 的拮抗剂，从而刺激甲状旁腺激素的释放[1]。
单独使用 fAβ25-35 处理皮层非致瘤性成人星形胶质细胞 (NAHA)，在 48 小时后，细胞因子和趋化因子释放到条件培养基中会显着增加。然而，NPS-2143(100nM) 可有效抑制细胞因子和趋化因子的分泌:IL-6、MCP-2、RANTES 和 s-ICAM-1 来自 NAHAs[2]。
NPS-2143 在 MDA-MB-231 和 MCF-7 细胞中显着降低细胞增殖，半数最大 (50%) 抑制浓度 (IC50) 值分别为 4.08 和 5.71 μM。 NPS-2143 在 MDA-MB-231 乳腺癌细胞中诱导 caspase 3/7 激活，同时 Bcl-2 抗凋亡蛋白的表达显着降低。 NPS-2143 抑制 MDA-MB-231 细胞的迁移和侵袭能力，显着降低 p-ERK1/2 和整合素 β1 蛋白的表达。NPS-2143 抑制乳腺癌细胞的增殖、迁移和侵袭作用，并伴有caspase 3/7 激活表明 NPS-2143 具有作为乳腺癌抗癌分子的潜力[3]。
NPS-2143 作为单次腹腔推注给药于野生型和 Nuf 小鼠，并测量钙和 PTH 的血浆浓度，并测量尿钙排泄。 NPS-2143 的体外给药纠正了与 Nuf 小鼠 CaSR 突变相关的功能获得。在 Nuf 小鼠中腹膜内注射 NPS-2143 可导致血浆钙和 PTH 显着增加，而不会增加尿钙排泄。这些对具有激活 CaSR 突变的小鼠模型的研究表明，NPS-2143 可使引起 ADH1 的功能获得正常化并改善与该疾病相关的低钙血症[4]。