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Background

Ruxolitinib (INCB18424), as an inhibitor, inhibits Janus-associated kinases (JAKs)JAK1 and JAK2 with IC₅₀ values of 3.3 nM and 2.8 nM, respectively. Ruxolitinib mediates several cytokine and growth factor signaling important for hematopoietic and immune function^[1-3].

Ruxolitinib (INCB18424) (500nM-50μM;30min) significantly inhibited the production of IL-6, TNF-α and MCP-1 as induced by A23817 and substance P in HMC1 cells^[4]. Ruxolitinib(0-400nM; 3days) reduced the level of cytokine release in CAR-T cells^[5].

Ruxolitinib (INCB18424) (30 mg/kg; p.o.; twice a day 14 days) treatment alleviated renal damage in UUO mice^[6]. Ruxolitinib(twice daily by oral gavage; 2 weeks) treatment improves viability and splenomegaly in a JAK2^V617F-driven model of malignant disease^[3]. Treatment of Fancc^-/- mice with ruxolitinib(45 mg/kg; i.p; 5 days/week) decreased anemia, enhanced granulocytosis, delayed clonal progression and prolonged survival during repeated emergency granulopoiesis episodes^[7].

參考文獻(xiàn):

[1]. Becker H, Engelhardt M, et,al. Ruxolitinib. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. PMID: 24756798.

[2]. Ajayi S, Becker H, et,al. Ruxolitinib. Recent Results Cancer Res. 2018;212:119-132. doi: 10.1007/978-3-319-91439-8_6. PMID: 30069628.

[3]. Quintás-Cardama A, Vaddi K, et,al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010 Apr 15;115(15):3109-17. doi: 10.1182/blood-2009-04-214957. Epub 2010 Feb 3. PMID: 20130243; PMCID: PMC3953826.

[4]. Hermans MAW, Schrijver B, et,al. The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release. Clin Exp Allergy. 2018 Nov;48(11):1412-1420. doi: 10.1111/cea.13217. Epub 2018 Aug 3. PMID: 29939445.

[5]. Xu N, Yang XF, et,al. Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells. Biochem Biophys Res Commun. 2022 Mar 5;595:54-61. doi: 10.1016/j.bbrc.2022.01.070. Epub 2022 Jan 20. PMID: 35101664.

[6]. Bai Y, Wang W, et,al. Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice. Int J Biol Sci. 2020 Jan 1;16(2):194-203. doi: 10.7150/ijbs.39024. PMID: 31929748; PMCID: PMC6949153.

[7]. Hasan S, Hu L, et,al. Ruxolitinib ameliorates progressive anemia and improves survival during episodes of emergency granulopoiesis in Fanconi C-/- mice. Exp Hematol. 2022 May;109:55-67.e2. doi: 10.1016/j.exphem.2022.03.001. Epub 2022 Mar 9. PMID: 35278531; PMCID: PMC9064927.

Ruxolitinib (INCB18424)作為一種抑制劑，能夠抑制Janus相關(guān)激酶(JAKs)JAK1和JAK2, IC₅₀ 分別為 3.3 nM 和 2.8 nM，Ruxolitinib介導(dǎo)對(duì)造血和免疫功能重要的若干細(xì)胞因子和生長因子信號(hào)^[1-3]。

Ruxolitinib (INCB18424) (500nM-50μM;30min)顯著抑制A23817和substance P誘導(dǎo)的HMC1細(xì)胞中IL-6、TNF-α和MCP-1的產(chǎn)生^[4]。Ruxolitinib (0-400nM; 3days)降低CAR-T細(xì)胞中細(xì)胞因子的釋放水平^[5]。

Ruxolitinib (INCB18424)治療(30 mg/kg; p.o.; twice a day 14 days)可減輕UUO小鼠腎損害^[6]。Ruxolitinib治療(twice daily by oral gavage; 2 weeks)改善JAK2^V617F-driven的惡性疾病小鼠的生存能力和脾腫大情況^[3]。用Ruxolitinib (45 mg/kg; i.p; 5 days/week)治療Fancc^-/-小鼠可減少貧血，增強(qiáng)粒細(xì)胞功能，延遲克隆進(jìn)展，延長反復(fù)緊急粒細(xì)胞生成發(fā)作期間的生存期^[7]。

Protocol

Cell experiment^[1]:
Cell lines	HMC1 cells
Preparation method	Cells were seeded in a 96-well plate at 2×10⁵ cells in 200 μL culture medium per condition. Subsequently, the cells were incubated for 30 minutes with ruxolitinib before stimulating them with 1 μmol/L of A23187 or 5 μmol/L of substance P. TNF-α levels in the supernatant were measured after 6 hours of stimulation, and MCP-1 and IL-6 levels were measured after 24 hours of stimulation.
Reaction Conditions	500nM-50μM;30min
Applications	Ruxolitinib significantly inhibited the production of IL-6, TNF-α and MCP-1 as induced by A23817 and substance P in HMC1 cells.
Animal experiment ^[2]:
Animal models	Male C57BL/6 mice
Preparation method	Mice were randomly assigned to three groups with 5 mice in each group as follows: (1) Sham-operated mice with vehicle (Sham); (2) Unilateral ureteral obstruction (UUO) mice with vehicle (UUO); (3) UUO mice treated with Ruxolitinib (UUO+RUX). To establish UUO model, mice were given general anesthesia by intraperitoneal injection of pentobarbital (50mg/kg body weight). The left ureter was exposed via a left flank incision, ligated with 4-0 silk at two points, and cut between the 2 ligation points. The Sham-operated group had no ligation. For in vivo experiments, Ruxolitinib was dissolved in PEG300/dextrose 5%l in a ratio of 1:3 (PEG/dex) and administered to mice by oral gavage at a dosage of 30 mg/kg twice daily for 14 days immediately after UUO or Sham-operation. The Sham and UUO group received PEG/dex alone as vehicle. Thel mice were sacrificed at days 14 after surgery.
Dosage form	30 mg/kg; p.o.; twice a day 14 days
Applications	Ruxolitinib treatment alleviated renal damage in UUO mice.
參考文獻(xiàn): [1]. Hermans MAW, Schrijver B, et,al. The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release. Clin Exp Allergy. 2018 Nov;48(11):1412-1420. doi: 10.1111/cea.13217. Epub 2018 Aug 3. PMID: 29939445. [2]. Bai Y, Wang W, et,al. Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice. Int J Biol Sci. 2020 Jan 1;16(2):194-203. doi: 10.7150/ijbs.39024. PMID: 31929748; PMCID: PMC6949153.