TAPI-1

TAPI-1 is a TACE (tumor necrosis factor-α converting enzyme) inhibitor that blocks the shedding of the extracellular domain of cell membrane proteins (amphiregulin (AREG)) mediated by TACE by inhibiting its proteolytic activity^{[1, 2]}. TAPI-1 is also a metalloproteinase (MMP) inhibitor^[3]. TAPI-1 can reduce cellular oxidative stress and the production of inflammatory factors^[4].

In vitro, TAPI-1 (0-20µM) treatment of TE-1 and Eca109 cells for 24h inhibited cell viability, migration, and invasion in a dose-dependent manner, and promoted cisplatin-induced apoptosis^[5]. TAPI-1 (20µM) treatment of A549 cells for 24h reduced cell proliferation and inhibited EGFR and Notch1 mRNA expression^[6]. TAPI-1 (5, 10µM) treatment of NCI-H292 cells for 6 and 24h blocked the shedding of amphiregulin (AREG) from the cell membrane stimulated by diacetyl^[7].

In vivo, TAPI-1 (10mg/kg) administered by intraperitoneal injection to mice with Staphylococcus aureus-induced arthritis significantly reduced paw swelling and decreased the concentrations of superoxide, nitric oxide, and hydrogen peroxide in joint tissues^[8].

References:
[1] Slack B E, Ma L K, Seah C C. Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-α converting enzyme[J]. Biochemical Journal, 2001, 357(3): 787-794.
[2] Liu C, Xu P, Lamouille S, et al. TACE-mediated ectodomain shedding of the type I TGF-β receptor downregulates TGF-β signaling[J]. Molecular cell, 2009, 35(1): 26-36.
[3] Koon H W, Zhao D, Na X, et al. Metalloproteinases and transforming growth factor-α mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes[J]. Journal of Biological Chemistry, 2004, 279(44): 45519-45527.
[4] Bae E H, Kim I J, Choi H S, et al. Tumor necrosis factor α-converting enzyme inhibitor attenuates lipopolysaccharide-induced reactive oxygen species and mitogen-activated protein kinase expression in human renal proximal tubule epithelial cells[J]. The Korean Journal of Physiology & Pharmacology, 2018, 22(2): 135-143.
[5] Gao L, Li L, Zhang D, et al. TAPI-1 exhibits Anti-tumor efficacy in human esophageal squamous cell carcinoma cells via suppression of NF-κB signaling pathway[J]. Digestive Diseases and Sciences, 2024, 69(1): 81-94.
[6] Pancewicz J, Golec P. The effect of TAPI-1 treatment in non-small cell lung cancer cells[J].
[7] Kelly F L, Sun J, Fischer B M, et al. Diacetyl induces amphiregulin shedding in pulmonary epithelial cells and in experimental bronchiolitis obliterans[J]. American journal of respiratory cell and molecular biology, 2014, 51(4): 568-574.
[8] Sultana S, Bishayi B. Potential anti-arthritic and anti-inflammatory effects of TNF-α processing inhibitor-1 (TAPI-1): A new approach to the treatment of S. aureus arthritis[J]. Immunobiology, 2020, 225(2): 151887.