In vivo antitumor effect of a triazolil peptidyl penicillin in murine melanoma cells

YANINA BELLIZZI; VIVIANA BLANK; PATRICIA G. CORNIER; CARINA M. DELPICCOLO; DORA B. BOGGIAN; ERNESTO G. MATA; LEONOR ROGUIN

Congreso; Reunion conjunta de sociedades de biociencias; 2017

The triazolylpeptidyl penicillins (TAP) are novel hybrids compoundshaving in their structure a penicillanic core linked to a peptideportion via a triazole group. In a previous study, we showedthat the derivative containing the dipeptide Leu-Phe (TAP6) inhibitedthe proliferation of mouse melanoma cells in vitro by arresting cellcycle and inducing an apoptotic response. In this work, we decidedto investigate the in vivo effectiveness of this derivative in a syngeneicC57BL/6J mouse melanoma model. To this end, B16-F0 cells(1x105) diluted in 200 μl of RPMI were injected subcutaneously inthe right flank of each mouse. 10-12 days after cell inoculation, micewere injected with 0.2 ml of vehicle (70 % (v/v) polyethylene glycol400 in PBS) or different doses of the penicillin derivative, via i.p.three times per week for two weeks. A dose-dependent effect wasevident, being the reduction of tumor volume ~70% and 50% at dosesof 20 and 10 mg/kg, respectively. A significant reduction of PCNAexpression, a cell proliferation marker, was detected in 20 mg/kgTAP6 treated- tumors. Apoptosis in vivo was also assessed by evaluatingthe expression of different apoptosis-mediator proteins. Thus,results obtained by Western blot showed a significant increment inthe expression levels of Bax (~2 fold), TRAIL (~1.5-fold) and Fas(~3.5-fold) proteins, and a significant decrease in the amount of fulllengthBid protein, Bcl-2, Bcl- XL and PARP in tumor lysates from20 mg/kg treated-mice. Immunohistochemistry assays of 20mg/kg treated-tumor slices revealed higher levels of active caspase-3.The administration of 80 mg/kg of TAP6 to non-tumor-bearing miceshowed no histopathological effects on different organ-tissues. Takentogether, our results showed that TAP6 markedly suppressedmelanoma cell proliferation in vivo by inducing an apoptotic celldeath. This novel penicillin derivative should be considered as apromising therapeutic agent for cancer treatmen