Tiplaxtinin(PAI-039) is an orally bioavailable antagonist of plasminogen activator inhibitor-1 (PAI-1) with IC50 value of 2.7μM. Tiplaxtinin is commonly employed in studies of antithrombosis, diabetic wound healing, and skeletal-muscle regeneration[1][2].
In vitro, the human cervical carcinoma (CC) cell lines HeLa and SiHa were treated with Tiplaxtinin at concentrations of 20µM, 40µM, 60µM, 80µM, and 100µM for 24h to72h. Tiplaxtinin showed a strong inhibitory effect on both SiHa and HeLa cells, significantly reducing their viability, colony formation, and migratory capacity[3]. Immortalized human keratinocytes HaCaT cells were incubated with 10µM Tiplaxtinin for 24h or 72h. Tiplaxtinin reduces PAI-1-stimulated keratinocyte migration in vitro while having no effect on epithelial proliferation, cell cycle progression, or apoptosis[4].
In vivo, male C57BL/6-Ins2 Akita/J mice were treated via oral gavage with vehicle (2% Tween-80 and 0.5% methylcellulose in sterile H2O) or vehicle plus Tiplaxtinin (2mg/kg) after becoming spontaneously diabetic at about 4 weeks of age due to a heterozygous mutation in the Ins-2 gene. Tiplaxtinin administration reversed the diabetic defect by promoting macrophage and satellite cell infiltration into necrotic areas of the tibialis anterior and gastrocnemius[5]. Tiplaxtinin (5mg/day) were orally administrated into mice model of chronic allergic asthma from 1 day before ovalbumin or PBS challenge until Day 36. Tiplaxtinin significantly reduced the bronchoalveolar lavage fluid levels of active PAI-1, the degree of inflammation, airway remodeling, and airway hyperresponsiveness in a murine model of chronic asthma[6]. Tiplaxtinin was administered by oral gavage to athymic mice bearing human bladder cancer cell line T24 xenografts and human cervical cancer HeLa cell xenografts. The subcutaneous tumor growth of both T24 and HeLa cell xenografts treated with tiplaxtinin was markedly reduced compared with untreated controls[7].
References:
[1] Hennan J K, Morgan G A, Swillo R E, et al. Effect of Tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis. J Thromb Haemost. 2008 Sep;6(9):1558-64.
[2] Rebalka I R, Raleigh M J, D'Souza D M, et al. Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes. Diabetes. 2015 Jul;64(7):2593-602.
[3] Wehbe S, Gallwas J, Gründker C. Inhibition of Plasminogen Activator Inhibitor-1 (PAI-1) by Tiplaxtinin Reduces Aggressiveness of Cervical Carcinoma Cells. Anticancer Res. 2025 May;45(5):1793-1805.
[4] Simone T M, Longmate W M, Law B K, Higgins P J. Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury. Adv Wound Care (New Rochelle). 2015 Jun 1;4(6):321-328.
[5] Krause M P, Sajee D A, D'Souza D M, et al. Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. PLoS One. 2013 Aug 12;8(8):e70971.
[6] Lee S H, Eren M, Vaughan D E, et al. A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma. Am J Respir Cell Mol Biol. 2012 Jun;46(6):842-6.
[7] Giacoia E G, Miyake M, Goodison S, Rosser C J. Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model. Mol Cancer Ther. 2013, Dec;12(12):2697-708.
Tiplaxtinin(PAI-039)是一种口服生物利用的尿激酶型纤溶酶原激活物抑制剂-1（PAI-1）拮抗剂，IC50值为2.7μM。Tiplaxtinin常被用于抗血栓、糖尿病伤口愈合和骨骼肌再生等研究[1][2]。
体外实验中，人宫颈癌细胞系HeLa和SiHa分别以20µM、40µM、60µM、80µM和100µM浓度的Tiplaxtinin处理24h至72h。Tiplaxtinin对SiHa和HeLa细胞表现出强烈抑制作用，显著降低其活力、集落形成能力和迁移能力[3]。永生化人角质形成细胞HaCaT以10µM Tiplaxtinin孵育24h或72h，Tiplaxtinin在体外抑制了PAI-1刺激的角质形成细胞迁移，而对上皮增殖、细胞周期进展或凋亡无影响[4]。
体内实验中，雄性C57BL/6-Ins2 Akita/J小鼠因Ins-2基因杂合突变于约4周龄自发形成糖尿病，随后经口灌胃给予空白对照溶媒(2%Tween-80和0.5%甲基纤维素无菌H2O)或溶媒加Tiplaxtinin(2mg/kg)。Tiplaxtinin给药通过促进巨噬细胞和卫星细胞浸润至胫骨前肌和腓肠肌坏死区域，逆转了糖尿病缺陷[5]。在慢性过敏性哮喘小鼠模型中，从卵清蛋白或PBS刺激前1天至第36天，每日口服给予Tiplaxtinin(5mg/day)。Tiplaxtinin显著降低支气管肺泡灌洗液中活性PAI-1水平、炎症程度、气道重塑及气道高反应性[6]。将Tiplaxtinin经口灌胃给予携带人膀胱癌细胞系T24异种移植物和人宫颈癌HeLa细胞异种移植物的裸鼠，T24和HeLa细胞异种移植物的皮下肿瘤生长较未处理对照显著减退[7]。