A Penicillin Derivative Exerts an Anti-Metastatic Activity in Melanoma Cells Through the Downregulation of Integrin αvβ3 and Wnt/β-Catenin Pathway

ELIZABETH BARRIONUEVO; FLORENCIA CAYROL; GRACIELA A. CREMASCHI; PATRICIA G. CORNIER; DORA B. BOGGIAN; CARINA M. DELPICCOLO; ERNESTO G. MATA; LEONOR P. ROGUIN; VIVIANA C. BLANK

Frontiers in Pharmacology

Frontiers Media

Lugar: Lausana; Año: 2020 vol. 11

The synthetic triazolylpeptidyl penicillin derivative, named TAP7f, has been previously characterized as an effective antitumor agent in vitro and in vivo against B16-F0 melanoma cells. In this study, we investigated the anti-metastatic potential of this compound on highly metastatic murine B16-F10 and human A375 melanoma cells. We found that TAP7f inhibited cell adhesion, migration and invasion in a dose-dependent manner. Additionally,we demonstrated that TAP7f downregulated integrin avb3 expression and Wnt/b-catenin pathway, a signaling cascade commonly related to tumor invasion and metastasis. Thus,TAP7f reduced both the enzymatic activity and the expression levels of matrixmetalloproteinases-2 and -9 in a time dependent manner. Moreover, TAP7f inhibited the expression of the transcription factor Snail and the mesenchymal markers vimentin, and N-cadherin, and up-regulated the expression of the epithelial marker E-cadherin, suggesting that the penicillin derivative affects epithelial?mesenchymal transition. Results obtained in vitro were supported by those obtained in a B16-F10-bearing mice metastatic model, that showed a significant TAP7f inhibition of lung metastasis. These findings suggest the potential of TAP7f as a chemotherapeutic agent for the treatment of metastatic melanoma.