Abstract 5256: Effect of the CIGB-300 synthetic peptide in the modulation of signaling pathways involved with malignant progression of human and murine lung tumors.

Abstract

Abstract CK2 is a serine/threonine kinase involved in cell growth, survival and apoptosis. The CIGB-300 is a synthetic peptide capable of binding to CK2 substrates thus preventing the enzyme activity. In this work we have studied the effect of IGBC-300 on several signaling pathways involved in tumor progression, cell cycle, apoptosis and biological effects associated metastatic dissemination, using a model of human and murine lung cancer cell lines (H125 and 3LL respectively). CIGB-300 presented a lethal dose 50 (LD50) of 119±2.4 μM in H125 cells and 138.3±9.9 μM in 3LL cells. Throughout an Annexin V-FITC assay we could determine that CIGB-300 is a potent apoptosis inductor since the treatment with this drug induced apoptosis at a level comparable with that induced by 10 μM of etoposide. Besides, concomitantly with cell death induction, we could observe the activation of caspase-3 and decreased expression of c-myc and cyclin D1 and D2. The levels of nuclear and cytoplasmic components of the Wnt and NFB pathways were analyzed by Western blot after treatment with CIGB-300. In the Wnt pathway, a significant decrease in nuclear β-catenin levels could be detected. Related to NFB pathway, a decrease in the nuclear p65 levels was observed, without affecting cytoplasmic levels of the IBα inhibitor. Both phenomena could be associated with a reduction in cell survival. Related to metastatic dissemination, we studied in vitro the effect of CIGB-300 on the modulation of the migratory capacity using a wound healing assay. CIGB-300 induced a significant reduction in the migratory potential in a dose dependent way in both 3LL cells (18.86 ± 2.2% vs 32.99 ± 2.7% ¼ and ½ LD50 respectively p <0.05) and H125 (31.73 ± 20.08% vs 51.12 ± 28.8% to ¼ and ½ LD50 respectively p <0.05). These results are in line with the reduction in urokinase secretion (28.64 ± 0.2% vs 44.19 ± 0.4% to ¼ and ½ LD50 respectively p <0.05) observed in the murine cell line 3LL treated with CIGB-300. Our results indicate that the treatment with CIGB-300 induces apoptosis and negatively modulates several signaling pathways involved in malignant progression besides affecting cell motility. This drug may become in the future a new strategy for the treatment of lung cancer, based on the blockade of different signaling pathways in lung cells. Citation Format: Alejandro J. Urtreger, Stefano M. Cirigliano, Maria I. Díaz Bessone, Carolina Flumián, Damian E. Berardi, Elisa D. Bal de Kier Joffé, Laura B. Todaro, Hernan G. Farina. Effect of the CIGB-300 synthetic peptide in the modulation of signaling pathways involved with malignant progression of human and murine lung tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5256. doi:10.1158/1538-7445.AM2013-5256