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Bufadienolides preferentially inhibit aminopeptidase N among mammalian metallo-aminopeptidases; relationship with effects on human melanoma MeWo cells

2022; Elsevier BV; Volume: 229; Linguagem: Inglês

10.1016/j.ijbiomac.2022.12.280

1879-0003

Isel Pascual Alonso, Laura Rivera Méndez, Fabiola Almeida García, Mario E. Valdés‐Tresanco, Roberto Alonso Bosch, Wilmer H. Perera, Yarini Arrebola Sánchez, Gretchen Bergado, Belinda Sánchez Ramírez, Jean-Louis Charlí,

Signaling Pathways in Disease

Bufadienolides are steroids that inhibit Na+/K+-ATPase; recent evidence shows that bufalin inhibits the activity of porcine aminopeptidase N (pAPN). We evaluated the selectivity of some bufadienolides on metallo-aminopeptidases. Among the enzymes of the M1 and M17 families, pAPN and porcine aminopeptidase A (pAPA) were the only targets of some bufadienolides. ѱ-bufarenogin, telocinobufagin, marinobufagin, bufalin, cinobufagin, and bufogenin inhibited the activity of pAPN in a dose-dependent manner in the range of 10-7-10-6 M. The inhibition mechanism was classical reversible noncompetitive for telocinobufagin, bufalin and cinobufagin. Bufogenin had the lowest Ki value and a non-competitive behavior. pAPA activity was inhibited by ѱ-bufarenogin, cinobufagin, and bufogenin, with a classical competitive type of inhibition. The models of enzyme-inhibitor complexes agreed with the non-competitive type of inhibition of pAPN by telocinobufagin, bufalin, cinobufagin, and bufogenin. Since APN is a target in cancer therapy, we tested the effect of bufadienolides on the MeWo APN+ human melanoma cell line; they induced cell death, but we obtained scant evidence that inhibition of APN contributed to their effect. Thus, APN is a selective target of some bufadienolides, and we suggest that inhibition of APN activity by bufadienolides is not a major contributor to their antiproliferative properties in MeWo cells.