Synergistic interactions of the anti‑casein kinase 2 CIGB‑300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Perera,Yasser; Del Toro,Neylen; Gorovaya,Larisa; Fernandez‑De‑Cossio,Jorge; Farina,Hernan  G.; Perea,Silvio  E.

doi:10.3892/mco.2014.338

Synergistic interactions of the anti‑casein kinase 2 CIGB‑300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Authors:
- Yasser Perera
- Neylen Del Toro
- Larisa Gorovaya
- Jorge Fernandez‑De‑Cossio
- Hernan G. Farina
- Silvio E. Perea
View Affiliations

Affiliations: Laboratory of Molecular Oncology, Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology (CIGB), Havana 10600, Cuba, Animal Facility Unit, Center for Genetic Engineering and Biotechnology (CIGB), Havana 10600, Cuba, Department of Bioinformatics, Center for Genetic Engineering and Biotechnology (CIGB), Havana 10600, Cuba, Laboratory of Molecular Oncology, Quilmes National University, Bernal, Buenos Aires B1876BXD, Argentina
Published online on: July 8, 2014 https://doi.org/10.3892/mco.2014.338
Pages: 935-944

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Guerra B and Issinger OG: Protein kinase CK2 in human diseases. Curr Med Chem. 15:1870–1886. 2008. View Article : Google Scholar : PubMed/NCBI
2	Ruzzene M and Pinna LA: Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta. 1804.499–504. 2010.PubMed/NCBI
3	Zandomeni R, Zandomeni MC, Shugar D and Weinmann R: Casein kinase type II is involved in the inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole of specific RNA polymerase II transcription. J Biol Chem. 261:3414–3419. 1986.PubMed/NCBI
4	Szyszka R, Grankowski N, Felczak K and Shugar D: Halogenated benzimidazoles and benzotriazoles as selective inhibitors of protein kinases CK I and CK II from Saccharomyces cerevisiae and other sources. Biochem Biophys Res Commun. 208:418–424. 1995.PubMed/NCBI
5	Sarno S, Reddy H, Meggio F, et al: Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 (‘casein kinase-2’). FEBS Lett. 496:44–48. 2001.
6	Pagano MA, Meggio F, Ruzzene M, Andrzejewska M, Kazimierczuk Z and Pinna LA: 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2. Biochem Biophys Res Commun. 321:1040–1044. 2004. View Article : Google Scholar : PubMed/NCBI
7	Duncan JS, Gyenis L, Lenehan J, Bretner M, Graves LM, Haystead TA and Litchfield DW: An unbiased evaluation of CK2 inhibitors by chemoproteomics: characterization of inhibitor effects on CK2 and identification of novel inhibitor targets. Mol Cell Proteomics. 7:1077–1088. 2008. View Article : Google Scholar : PubMed/NCBI
8	Pagano MA, Bain J, Kazimierczuk Z, et al: The selectivity of inhibitors of protein kinase CK2: an update. Biochem J. 415:353–365. 2008. View Article : Google Scholar : PubMed/NCBI
9	Marschke RF, Andreopoulou E, Von Hoff DD, Lim JK, Padgett CS and Northfelt DW: Phase I clinical trial of CX-4945: A first-in-class orally administered small molecule inhibitor of protein kinase CK2. Mol Cancer Ther. 8:C392009. View Article : Google Scholar
10	Siddiqui-Jain A, Drygin D, Streiner N, et al: CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 70:10288–10298. 2010. View Article : Google Scholar
11	Perea SE, Reyes O, Puchades Y, et al: Antitumor effect of a novel proapoptotic peptide that impairs the phosphorylation by the protein kinase 2 (casein kinase 2). Cancer Res. 64:7127–7129. 2004. View Article : Google Scholar : PubMed/NCBI
12	Perera Y, Farina HG, Gil J, et al: Anticancer peptide CIGB-300 binds to nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity. Mol Cancer Ther. 8:1189–1196. 2009. View Article : Google Scholar
13	Perera Y, Costales HC, Diaz Y, et al: Sensitivity of tumor cells towards CIGB-300 anticancer peptide relies on its nucleolar localization. J Pept Sci. 18:215–223. 2012. View Article : Google Scholar : PubMed/NCBI
14	Meggio F and Pinna LA: One-thousand-and-one substrates of protein kinase CK2? FASEB J. 17:349–368. 2003. View Article : Google Scholar : PubMed/NCBI
15	Rodriguez-Ulloa A, Ramos Y, Gil J, et al: Proteomic profile regulated by the anticancer peptide CIGB-300 in non-small cell lung cancer (NSCLC) cells. J Proteome Res. 9:5473–5483. 2010. View Article : Google Scholar : PubMed/NCBI
16	Farina HG, Benavent Acero F, Perera Y, et al: CIGB-300, a proapoptotic peptide, inhibits angiogenesis in vitro and in vivo. Exp Cell Res. 317:1677–1688. 2011. View Article : Google Scholar : PubMed/NCBI
17	Perera Y, Farina HG, Hernandez I, et al: Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in mice. Int J Cancer. 122:57–62. 2008. View Article : Google Scholar : PubMed/NCBI
18	Perea SE, Reyes O, Baladron I, et al: CIGB-300, a novel proapoptotic peptide that impairs the CK2 phosphorylation and exhibits anticancer properties both in vitro and in vivo. Mol Cell Biochem. 316:163–167. 2008. View Article : Google Scholar : PubMed/NCBI
19	Solares AM, Santana A, Baladron I, et al: Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies. BMC Cancer. 9:1462009. View Article : Google Scholar
20	Soriano-García JL, López-Díaz A, Solares-Asteasuainzarra M, et al: Pharmacological and safety evaluation of CIGB-300, a casein kinase 2 inhibitor peptide, administered intralesionally to patients with cervical cancer stage IB2/II. J Cancer Res Ther. 1:163–173. 2013.
21	Perea SE, Baladron I, Garcia Y, et al: CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research. Mol Cell Biochem. 356:45–50. 2011. View Article : Google Scholar : PubMed/NCBI
22	Al-Lazikani B, Banerji U and Workman P: Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 30:679–692. 2012. View Article : Google Scholar : PubMed/NCBI
23	Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 58:621–681. 2006. View Article : Google Scholar : PubMed/NCBI
24	Boyd M: The NCI In Vitro Anticancer Drug Discovery Screen. Concept, Implementation, and Operation, 1985–1995. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval. Humana Press; Totowa, NJ, USA: 1997
25	Chou TC and Hayball MP: CalcuSyn for Windows: multiple-drug dose effect analyzer and manual. Biosoft; Cambridge (UK): 1997
26	Kitano H: Cancer as a robust system: implications for anticancer therapy. Nat Rev Cancer. 4:227–235. 2004. View Article : Google Scholar : PubMed/NCBI
27	Dancey JE and Chen HX: Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov. 5:649–659. 2006. View Article : Google Scholar : PubMed/NCBI
28	Marupudi NI, Han JE, Li KW, Renard VM, Tyler BM and Brem H: Paclitaxel: a review of adverse toxicities and novel delivery strategies. Expert Opin Drug Saf. 6:609–621. 2007. View Article : Google Scholar : PubMed/NCBI
29	Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 13:180–190. 1995.PubMed/NCBI
30	Andersson A, Fagerberg J, Lewensohn R and Ehrsson H: Pharmacokinetics of cisplatin and its monohydrated complex in humans. J Pharm Sci. 85:824–827. 1996. View Article : Google Scholar : PubMed/NCBI
31	Kuenen BC, Rosen L, Smit EF, et al: Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol. 20:1657–1667. 2002. View Article : Google Scholar : PubMed/NCBI
32	Mayer LD and Janoff AS: Optimizing combination chemotherapy by controlling drug ratios. Mol Interv. 7:216–223. 2007. View Article : Google Scholar : PubMed/NCBI
33	Ohga T, Uchiumi T, Makino Y, Koike K, Wada M, Kuwano M and Kohno K: Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance 1 gene. J Biol Chem. 273:5997–6000. 1998. View Article : Google Scholar : PubMed/NCBI
34	Hennessy M and Spiers JP: A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol Res. 55:1–15. 2007. View Article : Google Scholar : PubMed/NCBI
35	Gaudreault I, Guay D and Lebel M: YB-1 promotes strand separation in vitro of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities and binds several DNA repair proteins. Nucleic Acids Res. 32:316–327. 2004. View Article : Google Scholar
36	Skabkin MA, Evdokimova V, Thomas AA and Ovchinnikov LP: The major messenger ribonucleoprotein particle protein p50 (YB-1) promotes nucleic acid strand annealing. J Biol Chem. 276:44841–44847. 2001. View Article : Google Scholar : PubMed/NCBI
37	Townsend DM and Tew KD: The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 22:7369–7375. 2003. View Article : Google Scholar : PubMed/NCBI
38	Pinna LA: Protein Kinase CK2. Wiley-Blackwell, . John Wiley & Sons, Inc; 2013, View Article : Google Scholar
39	Drygin D, Bliesath J, Ho C, et al: CX-4945, a novel small molecule inhibitor of CK2 protein kinase, reduces hyperactivated Akt signaling and synergizes with Akt inhibitors in breast cancer cells. In: 21st AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics; Boston, MA. Mol Cancer Ther. 8. pp. C1982009, View Article : Google Scholar
40	Bliesath J, Huser N, Omori M, et al: Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells. Cancer Lett. 322:113–118. 2012. View Article : Google Scholar : PubMed/NCBI
41	Siddiqui-Jain A, Bliesath J, Macalino D, et al: CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy. Mol Cancer Ther. 11:994–1005. 2012. View Article : Google Scholar
42	Siddiqui-Jain A, Streiner N, Bliesath J, et al: CX-4945, an inhibitor of protein kinase CK2, potentiates the antitumor activity of platinum chemotherapy in models of ovarian cancer by preventing phosphorylation of XRCC1 and MDC1 and disrupting DNA damage repair. Cancer Res. 71:54942011. View Article : Google Scholar