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

Abstract

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.

Apigenin-Loaded PLGA-DMSA Nanoparticles: A Novel Strategy to Treat Melanoma Lung Metastasis

“…Investigation of the 3D tumor spheroid penetration study showed higher cellular absorption of DMSA-conjugated APG nanoparticles as compared to the unconjugated nanoparticles. Thiol-containing DMSA can directly bind to cysteine of beta integrin receptors of the cells, , and that probably led to higher permeation and greater bioavailability of APG from DMSA-conjugated APG-NPs. Further, our investigation is also supported by the findings of Zhang et al that DMSA conjugation to nanoparticles improved bioavailability of nanoparticles …”

Scale-up synthesis of TAP7f, an antitumoral triazolyl peptidyl penicillin

“…In a preceding study, (2) we reported that derivative containing the dipeptide Leu-Phe (TAP7f, Figure 1), behaves as a selective and potent antitumor agent that induces an apoptotic response. (3,4) In order to support downstream research activities with this candidate, we were initially requested to prepare increasing amounts of TAP7f. Herein we describe the strategy chosen to achieve that goal.…”