Fernando Benavent Acero1, Carla S Capobianco2, Juan Garona3, Stéfano M Cirigliano4, Yasser Perera5, Alejandro J Urtreger6, Silvio E Perea7, Daniel F Alonso8, Hernan G Farina9. 1. Laboratory of Molecular Oncology, Quilmes National University, Roque Saenz Peña 352, Bernal CP1876, Buenos Aires, Argentina. Electronic address: ferbenavent@gmail.com. 2. Laboratory of Molecular Oncology, Quilmes National University, Roque Saenz Peña 352, Bernal CP1876, Buenos Aires, Argentina. Electronic address: cscapobianco@gmail.com. 3. Laboratory of Molecular Oncology, Quilmes National University, Roque Saenz Peña 352, Bernal CP1876, Buenos Aires, Argentina. Electronic address: juan.garona@unq.edu.ar. 4. Research Area, Institute of Oncology "Angel H. Roffo", University of Buenos Aires, Av. San Martín 5481, C1417DTB, Buenos Aires, Argentina. Electronic address: tefo.cirigliano@gmail.com. 5. Laboratory of Molecular Oncology, Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology (CIGB), La Havana, CP10600, PO Box 6162, Cuba. Electronic address: yasser.perera@cigb.edu.cu. 6. Research Area, Institute of Oncology "Angel H. Roffo", University of Buenos Aires, Av. San Martín 5481, C1417DTB, Buenos Aires, Argentina. Electronic address: urtreger@fmed.uba.ar. 7. Laboratory of Molecular Oncology, Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology (CIGB), La Havana, CP10600, PO Box 6162, Cuba. Electronic address: silvio.perea@cigb.edu.cu. 8. Laboratory of Molecular Oncology, Quilmes National University, Roque Saenz Peña 352, Bernal CP1876, Buenos Aires, Argentina. Electronic address: danielfalonso@gmail.com. 9. Laboratory of Molecular Oncology, Quilmes National University, Roque Saenz Peña 352, Bernal CP1876, Buenos Aires, Argentina. Electronic address: hgfarina@gmail.com.
Abstract
OBJECTIVES: Casein kinase 2 (CK2) is overexpressed in several types of cancer. It has more than 300 substrates mainly involved in DNA reparation and replication, chromatin remodeling and cellular growth. In recent years CK2 became an interesting target for anticancer drug development. CIGB-300 is a peptidic inhibitor of CK2 activity, designed to bind to the phospho-acceptor domain of CK2 substrates, impairing the correct phosphorylation by the enzyme. The aim of this work was to explore the antitumor effects of this inhibitor in preclinical lung cancer models. MATERIALS AND METHODS: Human H125 and murine 3LL Lewis lung carcinoma cell lines were used to evaluate the effect of CIGB-300 treatment in vitro. For this purpose, adhesion, migration and invasion capabilities of cancer cells were tested. Proteolytic activity of tumor cell-secreted uPA and MMP after CIGB-300 incubation was also analyzed. In vivo anticancer efficacy of the peptide was evaluated using experimental and spontaneous lung colonization assays in C57BL/6 mice. Finally, in order to test the effect of CIGB-300 on tumor cell-induced angiogenesis, a modified Matrigel plug assay was conducted. RESULTS AND CONCLUSION: We demonstrate that treatment with low micromolar concentrations of CIGB-300 caused a drastic reduction of adhesion, migration and invasion of lung cancer cells. Reduced invasiveness after CIGB-300 incubation was associated with decreased proteolytic activity of tumor cell-conditioned medium. In vivo, intravenous administration of CIGB-300 (10mg/kg) markly decreased lung colonization and metastasis development of 3LL cells. Interestingly, after 5days of systemic treatment with CIGB-300, tumor cell-driven neovascularization was significantly reduced in comparison to control group. Altogether our data suggest an important role of CK2 in lung tumor development, suggesting a potential use of CIGB-300 as a novel therapeutic agent against lung cancer.
OBJECTIVES:Casein kinase 2 (CK2) is overexpressed in several types of cancer. It has more than 300 substrates mainly involved in DNA reparation and replication, chromatin remodeling and cellular growth. In recent years CK2 became an interesting target for anticancer drug development. CIGB-300 is a peptidic inhibitor of CK2 activity, designed to bind to the phospho-acceptor domain of CK2 substrates, impairing the correct phosphorylation by the enzyme. The aim of this work was to explore the antitumor effects of this inhibitor in preclinical lung cancer models. MATERIALS AND METHODS:Human H125 and murine 3LL Lewis lung carcinoma cell lines were used to evaluate the effect of CIGB-300 treatment in vitro. For this purpose, adhesion, migration and invasion capabilities of cancer cells were tested. Proteolytic activity of tumor cell-secreted uPA and MMP after CIGB-300 incubation was also analyzed. In vivo anticancer efficacy of the peptide was evaluated using experimental and spontaneous lung colonization assays in C57BL/6 mice. Finally, in order to test the effect of CIGB-300 on tumor cell-induced angiogenesis, a modified Matrigel plug assay was conducted. RESULTS AND CONCLUSION: We demonstrate that treatment with low micromolar concentrations of CIGB-300 caused a drastic reduction of adhesion, migration and invasion of lung cancer cells. Reduced invasiveness after CIGB-300 incubation was associated with decreased proteolytic activity of tumor cell-conditioned medium. In vivo, intravenous administration of CIGB-300 (10mg/kg) markly decreased lung colonization and metastasis development of 3LL cells. Interestingly, after 5days of systemic treatment with CIGB-300, tumor cell-driven neovascularization was significantly reduced in comparison to control group. Altogether our data suggest an important role of CK2 in lung tumor development, suggesting a potential use of CIGB-300 as a novel therapeutic agent against lung cancer.
Authors: Stéfano M Cirigliano; María I Díaz Bessone; Damián E Berardi; Carolina Flumian; Elisa D Bal de Kier Joffé; Silvio E Perea; Hernán G Farina; Laura B Todaro; Alejandro J Urtreger Journal: Cancer Cell Int Date: 2017-03-31 Impact factor: 5.722
Authors: Maria F Gottardo; Carla S Capobianco; Johanna E Sidabra; Juan Garona; Yasser Perera; Silvio E Perea; Daniel F Alonso; Hernan G Farina Journal: Sci Rep Date: 2020-09-07 Impact factor: 4.379