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.