J Pharm Pharmacogn Res 2(Suppl. 1): S5, 2014
Special supplement with the abstract book of LATINFARMA 2013
CO 009: A NOVEL PEPTIDE SELECTED FROM AN ALASCANNING REGULATES THE ONCOGENIC ACTIVITY OF NFKB IN CANCER CELLS
Oliva B, Fernandez Jr, Gil J, Garay H, Reyes O, Guillen G, Vallespi GM.
Introduction: The nuclear factor NFkB plays a critical role in diverse cellular processes associated with proliferation, cell death, as well as inflammation. Starting from a LPS-binding peptide from Limulus antiLPS factor, with powerful immunostimulatory activity, we have done alanine substitutions of particular residues and obtained a novel synthetic peptide (CIGB-552) that has lost its LPS binding capacity and is a powerful in vitro and in vivo cytotoxic agent. The potential mechanism responsible for the antitumor activity of CIGB-552 is based on a specific degradation of RelA (p65) and inhibition of NFkB regulated genes.
Material and methods: Cell lines: HT-29 (human colon cancer) and D122 (Lewis lung carcinoma). Female Balb/c mice were purchased from CENPALAB, Cuba. The peptide was synthesized manually using Fmoc/tBu solid phase.
Results: Here we demonstrate that treatment of tumor cells with the peptide CIGB-552 promotes the degradation of RelA (p65) and induces cell cycle arrest and apoptosis. In addition, the peptide inhibits gene products activated by NFkB, such as the anti-apoptotic protein Bcl-2. Here, we demonstrate that the CIGB-552 stabilizes a key protein in tumor cells, it which inhibits the transcription activity of NFkB. These findings provide evidence to support the regulation of transcription factor NFkB by the peptide CIGB- 552 in cancer cells. Furthermore, we demonstrate that CIGB-552 decrease tumor growth and increase survival in the human colon cancer xenograft HT-29 and shows anti-metastatic activity in a spontaneous metastatic model of the Lewis lung carcinoma.
Conclusion: Our finding points out to a novel mechanism by which the anti-apoptotic activity of NFkB can be regulated in cancer cells. Better understanding of the regulation of NFkB will provide a platform for development of specific therapeutic agents targeted towards the cancer-associated inflammation.