A novel penicillin derivative induces antitumor effect in melanoma cells

Abstract

In this study, we explored the in-vitro and in-vivo mechanism of antitumor action of a novel synthetic nonantibiotic triazolylpeptidyl penicillin derivative, named TAP7f, on B16-F0 murine melanoma cells. In-vitro assays showed that TAP7f caused an inhibition of S phase progression and a concomitant decrease of the percentage of cells in G0/G1 phase. We also found that TAP7f treatment induced an apoptotic response characterized by an increase of the sub-G1 fraction of B16-F0 hypodiploid cells, the occurrence of cells with picnotic nuclei, and the detection of phosphatidylserine exposure on the outer side of the plasma membrane. Apoptotic cell death was further characterized by the activation of caspase-8, caspase-9, and caspase-3; the increase in the proapoptotic/antiapoptotic ratio of Bcl-2 family proteins; the higher expression levels of Fas receptor and TRAIL ligand; and the cleavage of poly(ADP-ribose) polymerase, a caspase-3 substrate. The in-vivo effect of TAP7f was studied in a syngeneic C57BL/6J mouse melanoma model. Results showed that TAP7f inhibited melanoma cell proliferation in vivo, as determined by a decreased expression of proliferating cell nuclear antigen, inducing a significant reduction of tumor growth. Apoptosis in vivo was assessed by detecting active caspase-3 in tumor slices from treated mice and the expression levels of Fas, TRAIL, and Bcl-2 proteins in tumor lysates. The administration of 80 mg/kg of TAP7f to non-tumor-bearing mice showed no histopathological effects on different organ tissues. Our results suggest that TAP7f might be considered as a potential therapeutic agent for cancer treatment.

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

“…In a previous work, we have examined the in vitro antitumor action of the non-antibiotic triazolyl penicillin derivative TAP7f in different non metastatic human and murine adenocarcinoma cell lines (Blank et al, 2018). We also demonstrated the in vivo efficacy of this derivative in a murine melanoma model (Blank et al, 2018). In this work, we reported for the first time the anti-metastatic properties of TAP7f against highly metastatic melanoma cells in vitro and in vivo.…”

“…We have also demonstrated that TAP7f induced an antitumor effect through the induction of cell cycle arrest and the activation of both death receptor and mitochondria-dependent apoptotic pathways in melanoma B16-F0 cells (Blank et al, 2018). Moreover, when TAP7f was evaluated in vivo in a B16-F0 murine melanoma model, results showed a reduction of approximately 70% of tumor growth (Blank et al, 2018). In order to continue exploring TAP7f biological properties, we herein investigated the in vitro antimetastatic effect of this compound in murine B16-F10 and human A375 melanoma cells.…”

“…The triazolylpeptidyl penicillin derivative TAP7f, with leucine and phenylalanine bound to the triazole group, was the most potent and selective TAP tested, showing 30 times more antiproliferative activity on tumor cells than on normal cells (Cornier et al, 2014). We have also demonstrated that TAP7f induced an antitumor effect through the induction of cell cycle arrest and the activation of both death receptor and mitochondria-dependent apoptotic pathways in melanoma B16-F0 cells (Blank et al, 2018). Moreover, when TAP7f was evaluated in vivo in a B16-F0 murine melanoma model, results showed a reduction of approximately 70% of tumor growth (Blank et al, 2018).…”

“…Therefore, there is an urgent need to find drugs aimed at blocking one or more steps of the metastatic cascade. In a previous work, we have examined the in vitro antitumor action of the non-antibiotic triazolyl penicillin derivative TAP7f in different non metastatic human and murine adenocarcinoma cell lines (Blank et al, 2018). We also demonstrated the in vivo efficacy of this derivative in a murine melanoma model (Blank et al, 2018).…”

“…We have previously reported that TAP7f induces an antiproliferative activity on different tumor cell lines (Cornier et al, 2014;Blank et al, 2018). In this work, we explored TAP7f effect on the proliferation of metastatic cells from different sources ( Table 1).…”