Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models
Authors:
Open Access
- 8 July 2014
- journal article
- Published by Spandidos Publications in Molecular and Clinical Oncology
- Vol. 2 (6) , 935-944
Abstract
CIGB‑300 is a novel clinical‑stage synthetic peptide that impairs the casein kinase 2 (CK2)‑mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB‑300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. in this study, we investigated the antiproliferative effect of CIGB‑300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5‑fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by Calcusyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB‑300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose‑finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB‑300 and cisplatin increased mice survival compared to single‑agent treatment. Collectively, these findings provide a rationale for combining the anti‑CK2 CIGB‑300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.Keywords
This publication has 39 references indexed in Scilit:
- CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination TherapyMolecular Cancer Therapeutics, 2012
- CX-4945, an Orally Bioavailable Selective Inhibitor of Protein Kinase CK2, Inhibits Prosurvival and Angiogenic Signaling and Exhibits Antitumor EfficacyCancer Research, 2010
- Proteomic Profile Regulated by the Anticancer Peptide CIGB-300 in Non-Small Cell Lung Cancer (NSCLC) CellsJournal of Proteome Research, 2010
- Addiction to protein kinase CK2: A common denominator of diverse cancer cells?Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2010
- Safety and preliminary efficacy data of a novel Casein Kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignanciesBMC Cancer, 2009
- Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in miceInternational Journal of Cancer, 2007
- Antitumor Effect of a Novel Proapoptotic Peptide that Impairs the Phosphorylation by the Protein Kinase 2 (Casein Kinase 2)Cancer Research, 2004
- The Major Messenger Ribonucleoprotein Particle Protein p50 (YB-1) Promotes Nucleic Acid Strand AnnealingJournal of Biological Chemistry, 2001
- Selectivity of 4,5,6,7‐tetrabromobenzotriazole, an ATP site‐directed inhibitor of protein kinase CK2 (‘casein kinase‐2’)FEBS Letters, 2001
- Halogenated Benzimidazoles and Benzotriazoles as Selective Inhibitors of Protein Kinases CK-I and CK-II from Saccharomyces Cerevisiae and Other SourcesBiochemical and Biophysical Research Communications, 1995