A novel penicillin derivative induces antitumor effect in melanoma cells

BLANK VC; CORNIER P.G.; BLANK VC; CORNIER P.G.; BOGGIÁN D.B; ROGUIN, L. P; BOGGIÁN D.B; ROGUIN, L. P; BELLIZZI YANINA; MATA E.G.; BELLIZZI YANINA; MATA E.G.

ANTICANCER DRUGS

LIPPINCOTT WILLIAMS & WILKINS

Lugar: Philadelphia; Año: 2018 p. 416 - 428

0959-4973

In this study we explored the in vitro and in vivo mechanism of antitumor action of a novel synthetic non-antibiotic 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, -9 and -3, the increase in the pro-apoptotic/anti-apoptotic ratio of Bcl-2 family proteins, the higher expression levels of Fas receptor and TRAIL ligand, and the cleavage of PARP, 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 PCNA, 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.