In vivo antitumor efect of a triazolyl peptidyl penicillin in murine melanoma cells

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

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC. SAI. SAFE. SAA. SAIB. SAB. SAFIS.SAP. SAH

The triazolylpeptidyl penicillins (TAP) are novel hybrids compounds having in their structure a penicillanic core linked to a peptide portion via a triazole group. In a previous study, we showed that the derivative containing the dipeptide Leu-Phe (TAP6) inhibited the proliferation of mouse melanoma cells in vitro by arresting cell cycle and inducing an apoptotic response. In this work, we decided to investigate the in vivo effectiveness of this derivative in a syngeneic C57BL/6J mouse melanoma model. To this end, B16-F0 cells (1x105) diluted in 200 µl of RPMI were injected subcutaneously in the right flank of each mouse. 10-12 days after cell inoculation, mice were injected with 0.2 ml of vehicle (70 % (v/v) polyethylene glycol 400 in PBS) or different doses of the penicillin derivative, via i.p. three times per week for two weeks. A dose-dependent effect was evident, being the reduction of tumor volume 70% and 50% at doses of 20 and 10 mg/kg, respectively. A significant reduction of PCNA expression, a cell proliferation marker, was detected in 20 mg/kg TAP6 treated- tumors. Apoptosis in vivo was also assessed by evaluating the expression of different apoptosis-mediator proteins. Thus, results obtained by Western blot showed a significant increment in the expression levels of Bax (2 fold), TRAIL (1.5-fold) and Fas (3.5-fold) proteins, and a significant decrease in the amount of full-length Bid protein, Bcl-2, Bcl- XL and PARP in tumor lysates from 20 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 mice showed no histopathological effects on different organ-tissues. Taken together, our results showed that TAP6 markedly suppressed melanoma cell proliferation in vivo by inducing an apoptotic cell death. This novel penicillin derivative should be considered as a promising therapeutic agent for cancer treatment.