Targeting CK2 for Cancer Therapy Using a Nanomedicine Approach

  • Khalil Ahmed
  • Gretchen Unger
  • Betsy T. Kren
  • Janeen H. TrembleyEmail author
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 12)


CK2 is a signal-responsive serine/threonine protein kinase which promotes cell proliferation, suppresses apoptosis, and demonstrates increased expression in numerous cancers. Here, we present information on investigations into CK2-focused cancer therapy in general and discuss in detail a nanomedicine approach to targeting CK2 in a cancer cell-specific manner. Specifically, we summarize data on biodistribution and therapeutic efficacy of a tenfibgen (TBG) nanoencapsulation technology for the delivery of anti-CK2 cargos to malignant cells. The TBG nanocapsule cargos discussed include siRNA (siCK2), single-stranded DNA/RNA chimeric oligonucleotides (RNAi-CK2), and a small-molecule CK2 inhibitor (DMAT). Systemic administration of TBG-RNAi-CK2 resulted in xenograft tumor reduction using low doses with concomitant reduction in CK2 protein expression. Systemic TBG-DMAT treatment decreased xenograft tumor proliferation. No toxicity or early inflammation response was observed after using any of the TBG encapsulated anti-CK2 cargos. The utility of this therapy approach for targeting metastatic cancer sites and on overall survival is also discussed. Protected and malignant cell-specific delivery of a therapeutic is a promising target-specific and versatile approach for cancer therapy, and both the TBG encapsulation technology and the anti-CK2 oligonucleotide approach demonstrate substantial potential for the treatment of malignancy.


CK2 Antisense RNAi siRNA DMAT Nanocapsule Nanoparticle Nanomedicine Xenograft Prostate HNSCC Biodistribution Metastasis 


  1. 1.
    Gapany M, Faust RA, Tawfic S, Davis A, Adams GL, Ahmed K (1995) Association of elevated protein kinase CK2 activity with aggressive behavior of squamous cell carcinoma of the head and neck. Mol Med 1(6):659–666PubMedCentralPubMedGoogle Scholar
  2. 2.
    Faust RA, Gapany M, Tristani P, Davis A, Adams GL, Ahmed K (1996) Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cancer Lett 101(1):31–35. doi: 10.1016/0304-3835(96)04110-9 CrossRefPubMedGoogle Scholar
  3. 3.
    Faust RA, Niehans G, Gapany M, Hoistad D, Knapp D, Cherwitz D, Davis A, Adams GL, Ahmed K (1999) Subcellular immunolocalization of protein kinase CK2 in normal and carcinoma cells. Int J Biochem Cell Biol 31(9):941–949. doi: 10.1016/S1357-2725(99)00050-3 CrossRefPubMedGoogle Scholar
  4. 4.
    Faust RA, Tawfic S, Davis AT, Bubash LA, Ahmed K (2000) Antisense oligonucleotides against protein kinase CK2-α inhibit growth of squamous cell carcinoma of the head and neck in vitro. Head Neck 22(4):341–346. doi: 10.1002/1097-0347(200007)22:4<341::AID-HED5>3.0.CO;2-3 [pii] CrossRefPubMedGoogle Scholar
  5. 5.
    Wang H, Davis A, Yu S, Ahmed K (2001) Response of cancer cells to molecular interruption of the CK2 signal. Mol Cell Biochem 227(1–2):167–174. doi: 10.1023/A:1013112908734 CrossRefPubMedGoogle Scholar
  6. 6.
    Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K (2001) Protein kinase CK2 signal in neoplasia. Histol Histopathol 16(2):573–582PubMedGoogle Scholar
  7. 7.
    Guo C, Yu S, Davis AT, Wang H, Green JE, Ahmed K (2001) A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells. J Biol Chem 276(8):5992–5999. doi: 10.1074/jbc.M004862200 CrossRefPubMedGoogle Scholar
  8. 8.
    Wang G, Ahmad KA, Ahmed K (2006) Role of protein kinase CK2 in the regulation of tumor necrosis factor-related apoptosis inducing ligand-induced apoptosis in prostate cancer cells. Cancer Res 66(4):2242–2249. doi: 10.1158/0008-5472.CAN-05-2772, 66/4/2242 [pii]CrossRefPubMedGoogle Scholar
  9. 9.
    Yu S, Wang H, Davis A, Ahmed K (2001) Consequences of CK2 signaling to the nuclear matrix. Mol Cell Biochem 227(1–2):67–71. doi: 10.1023/A:1013156721938 CrossRefPubMedGoogle Scholar
  10. 10.
    Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12(5):226–230. doi: 10.1016/S0962-8924(02)02279-1 CrossRefPubMedGoogle Scholar
  11. 11.
    Wang G, Ahmad KA, Ahmed K (2005) Modulation of death receptor-mediated apoptosis by CK2. Mol Cell Biochem 274(1–2):201–205CrossRefPubMedGoogle Scholar
  12. 12.
    Wang G, Unger G, Ahmad KA, Slaton JW, Ahmed K (2005) Downregulation of CK2 induces apoptosis in cancer cells–a potential approach to cancer therapy. Mol Cell Biochem 274(1–2):77–84CrossRefPubMedGoogle Scholar
  13. 13.
    Ahmad KA, Wang G, Slaton J, Unger G, Ahmed K (2005) Targeting CK2 for cancer therapy. Anticancer Drugs 16(10):1037–1043. doi: 10.1097/00001813-200511000-00001 CrossRefPubMedGoogle Scholar
  14. 14.
    Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17(3):349–368. doi: 10.1096/fj.02-0473rev CrossRefPubMedGoogle Scholar
  15. 15.
    Marchiori F, Meggio F, Marin O, Borin G, Calderan A, Ruzza P, Pinna LA (1988) Synthetic peptide substrates for casein kinase 2. Assessment of minimum structural requirements for phosphorylation. Biochim Biophys Acta 971(3):332–338CrossRefPubMedGoogle Scholar
  16. 16.
    Faust M, Montenarh M (2000) Subcellular localization of protein kinase CK2. A key to its function? Cell Tissue Res 301(3):329–340CrossRefPubMedGoogle Scholar
  17. 17.
    Yu S, Davis AT, Guo C, Green JE, Ahmed K (1999) Differential targeting of protein kinase CK2 to the nuclear matrix upon transient overexpression of its subunits. J Cell Biochem 74(1):127–134. doi: 10.1002/(SICI)1097-4644(19990701)74:1<127::AID-JCB14>3.0.CO;2-3 CrossRefPubMedGoogle Scholar
  18. 18.
    Ahmed K, Yenice S, Davis A, Goueli SA (1993) Association of casein kinase 2 with nuclear chromatin in relation to androgenic regulation of rat prostate. Proc Natl Acad Sci U S A 90(10):4426–4430CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Trembley JH, Wang G, Unger G, Slaton J, Ahmed K (2009) Protein kinase CK2 in health and disease: CK2: a key player in cancer biology. Cell Mol Life Sci 66(11–12):1858–1867. doi: 10.1007/s00018-009-9154-y CrossRefPubMedGoogle Scholar
  20. 20.
    Niefind K, Issinger OG (2010) Conformational plasticity of the catalytic subunit of protein kinase CK2 and its consequences for regulation and drug design. Biochim Biophys Acta 1804(3):484–492. doi: 10.1016/j.bbapap.2009.09.022, S1570-9639(09)00270-2 [pii]CrossRefPubMedGoogle Scholar
  21. 21.
    le Nguyen XT, Mitchell BS (2013) Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA. Proc Natl Acad Sci U S A 110(51):20681–20686. doi: 10.1073/pnas.1313097110 CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Tarrant MK, Rho HS, Xie Z, Jiang YL, Gross C, Culhane JC, Yan G, Qian J, Ichikawa Y, Matsuoka T, Zachara N, Etzkorn FA, Hart GW, Jeong JS, Blackshaw S, Zhu H, Cole PA (2012) Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis. Nat Chem Biol 8(3):262–269. doi: 10.1038/nchembio.771 CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA (2013) PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol Cell Biol 33(16):3091–3098. doi: 10.1128/MCB. 00319-13 CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Nolen B, Taylor S, Ghosh G (2004) Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell 15(5):661–675. doi: 10.1016/j.molcel.2004.08.024 CrossRefPubMedGoogle Scholar
  25. 25.
    Padmanabha R, Chen-Wu JL, Hanna DE, Glover CV (1990) Isolation, sequencing, and disruption of the yeast CKA2 gene: casein kinase II is essential for viability in Saccharomyces cerevisiae. Mol Cell Biol 10(8):4089–4099PubMedCentralPubMedGoogle Scholar
  26. 26.
    Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB, Cochet C, Issinger OG, Boldyreff B (2003) Disruption of the regulatory β subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23(3):908–915CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Seldin DC, Lou DY, Toselli P, Landesman-Bollag E, Dominguez I (2008) Gene targeting of CK2 catalytic subunits. Mol Cell Biochem 316(1–2):141–147. doi: 10.1007/s11010-008-9811-8 CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Fraser AG, Kamath RS, Zipperlen P, Martinez-Campos M, Sohrmann M, Ahringer J (2000) Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408(6810):325–330CrossRefPubMedGoogle Scholar
  29. 29.
    Trembley JH, Chen Z, Unger G, Slaton J, Kren BT, Van Waes C, Ahmed K (2010) Emergence of protein kinase CK2 as a key target in cancer therapy. Biofactors 36(3):187–195. doi: 10.1002/biof.96 CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Ruzzene M, Pinna LA (2010) Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta 1804(3):499–504. doi: 10.1016/j.bbapap.2009.07.018 CrossRefPubMedGoogle Scholar
  31. 31.
    Guerra B, Issinger OG (2008) Protein kinase CK2 in human diseases. Curr Med Chem 15(19):1870–1886. doi: 10.1007/s00018-009-9148-9 CrossRefPubMedGoogle Scholar
  32. 32.
    Munstermann U, Fritz G, Seitz G, Lu YP, Schneider HR, Issinger OG (1990) Casein kinase II is elevated in solid human tumours and rapidly proliferating non-neoplastic tissue. Eur J Biochem 189(2):251–257CrossRefPubMedGoogle Scholar
  33. 33.
    Pistorius K, Seitz G, Remberger K, Issinger OG (1991) Differential CKII activities in human colorectal mucosa, adenomas and carcinomas. Onkologie 14(3):256–260CrossRefGoogle Scholar
  34. 34.
    Mandal T, Bhowmik A, Chatterjee A, Chatterjee U, Chatterjee S, Ghosh MK (2014) Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2 - protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal 26(8):1725–1734. doi: 10.1016/j.cellsig.2014.04.003 CrossRefPubMedGoogle Scholar
  35. 35.
    Giusiano S, Cochet C, Filhol O, Duchemin-Pelletier E, Secq V, Bonnier P, Carcopino X, Boubli L, Birnbaum D, Garcia S, Iovanna J, Charpin C (2011) Protein kinase CK2alpha subunit over-expression correlates with metastatic risk in breast carcinomas: quantitative immunohistochemistry in tissue microarrays. Eur J Cancer 47(5):792–801. doi: 10.1016/j.ejca.2010.11.028 CrossRefPubMedGoogle Scholar
  36. 36.
    O-charoenrat P, Rusch V, Talbot SG, Sarkaria I, Viale A, Socci N, Ngai I, Rao P, Singh B (2004) Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung. Clin Cancer Res 10(17):5792–5803. doi: 10.1158/1078-0432.CCR-03-0317 CrossRefPubMedGoogle Scholar
  37. 37.
    Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes JL, Cochet C (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2α) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer 43(5):928–934. doi: 10.1016/j.ejca.2006.11.021 CrossRefPubMedGoogle Scholar
  38. 38.
    Kim JS, Eom JI, Cheong J-W, Choi AJ, Lee JK, Yang WI, Min YH (2007) Protein kinase CK2α as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res 13(3):1019–1028. doi: 10.1158/1078-0432.ccr-06-1602 CrossRefPubMedGoogle Scholar
  39. 39.
    Lin KY, Fang CL, Chen Y, Li CF, Chen SH, Kuo CY, Tai C, Uen YH (2010) Overexpression of nuclear protein kinase CK2 Beta subunit and prognosis in human gastric carcinoma. Ann Surg Oncol 17(6):1695–1702. doi: 10.1245/s10434-010-0911-9 CrossRefPubMedGoogle Scholar
  40. 40.
    Lin KY, Tai C, Hsu JC, Li CF, Fang CL, Lai HC, Hseu YC, Lin YF, Uen YH (2011) Overexpression of nuclear protein kinase CK2 alpha catalytic subunit (CK2alpha) as a poor prognosticator in human colorectal cancer. PLoS One 6(2):e17193. doi: 10.1371/journal.pone.0017193 CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Zheng Y, McFarland BC, Drygin D, Yu H, Bellis SL, Kim H, Bredel M, Benveniste EN (2013) Targeting protein kinase CK2 suppresses prosurvival signaling pathways and growth of glioblastoma. Clin Cancer Res 19(23):6484–6494. doi: 10.1158/1078-0432.ccr-13-0265 CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Gray GK, McFarland BC, Rowse AL, Gibson SA, Benveniste EN (2014) Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells. Oncotarget 5(15):6484–6496PubMedCentralPubMedGoogle Scholar
  43. 43.
    Ulloa L, Diaz-Nido J, Avila J (1993) Depletion of casein kinase II by antisense oligonucleotide prevents neuritogenesis in neuroblastoma cells. EMBO J 12(4):1633–1640PubMedCentralPubMedGoogle Scholar
  44. 44.
    Formby B, Stern R (1998) Phosphorylation stabilizes alternatively spliced CD44 mRNA transcripts in breast cancer cells: inhibition by antisense complementary to casein kinase II mRNA. Mol Cell Biochem 187(1):23–30CrossRefPubMedGoogle Scholar
  45. 45.
    Seeber S, Issinger OG, Holm T, Kristensen LP, Guerra B (2005) Validation of protein kinase CK2 as oncological target. Apoptosis 10(4):875–885. doi: 10.1007/s10495-005-0380-y CrossRefPubMedGoogle Scholar
  46. 46.
    Trembley JH, Unger GM, Tobolt DK, Korman VL, Wang G, Ahmad KA, Slaton JW, Kren BT, Ahmed K (2011) Systemic administration of antisense oligonucleotides simultaneously targeting CK2alpha and alpha’ subunits reduces orthotopic xenograft prostate tumors in mice. Mol Cell Biochem 356:21–35. doi: 10.1007/s11010-011-0943-x CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Quotti Tubi L, Gurrieri C, Brancalion A, Bonaldi L, Bertorelle R, Manni S, Pavan L, Lessi F, Zambello R, Trentin L, Adami F, Ruzzene M, Pinna LA, Semenzato G, Piazza F (2013) Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. J Hematol Oncol 6:78. doi: 10.1186/1756-8722-6-78 CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Zhang S, Wang Y, Mao J-H, Hsieh D, Kim I-J, Hu L-M, Xu Z, Long H, Jablons DM, You L (2012) Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells. PLoS One 7(6):e38996. doi: 10.1371/journal.pone.0038996 CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Ko H, Kim S, Jin CH, Lee E, Ham S, Yook JI, Kim K (2012) Protein kinase casein kinase 2-mediated upregulation of N-cadherin confers anoikis resistance on esophageal carcinoma cells. Mol Cancer Res 10(8):1032–1038. doi: 10.1158/1541-7786.MCR-12-0261 CrossRefPubMedGoogle Scholar
  50. 50.
    Zhang S, Long H, Yang Y-L, Wang Y, Hsieh D, Li W, Au A, Stoppler HJ, Xu Z, Jablons DM, You L (2013) Inhibition of CK2α down-regulates Notch1 signalling in lung cancer cells. J Cell Mol Med 17(7):854–862. doi: 10.1111/jcmm.12068 CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Trembley JH, Unger GM, Korman VL, Tobolt DK, Kazimierczuk Z, Pinna LA, Kren BT, Ahmed K (2012) Nanoencapsulated anti-CK2 small molecule drug or siRNA specifically targets malignant cancer but not benign cells. Cancer Lett 315(1):48–58. doi: 10.1016/j.canlet.2011.10.007 CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Kreutzer J, Ruzzene M, Guerra B (2010) Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells. BMC Cancer 10(1):440CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Brown MS, Diallo OT, Hu M, Ehsanian R, Yang X, Arun P, Lu H, Korman V, Unger G, Ahmed K, Van Waes C, Chen Z (2010) CK2 modulation of NF-κB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub–50-nm nanocapsules. Clin Cancer Res 16(8):2295–2307. doi: 10.1158/1078-0432.ccr-09-3200 CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Kang JY, Kim JJ, Jang SY, Bae YS (2009) The p53-p21(Cip1/WAF1) pathway is necessary for cellular senescence induced by the inhibition of protein kinase CKII in human colon cancer cells. Mol Cells 28(5):489–494. doi: 10.1007/s10059-009-0141-9 CrossRefPubMedGoogle Scholar
  55. 55.
    Schneider CC, Hessenauer A, Montenarh M, Gotz C (2010) p53 is dispensable for the induction of apoptosis after inhibition of protein kinase CK2. Prostate 70(2):126–134. doi: 10.1002/pros.21044 PubMedGoogle Scholar
  56. 56.
    Cozza G, Pinna LA, Moro S (2013) Kinase CK2 inhibition: an update. Curr Med Chem 20(5):671–693CrossRefPubMedGoogle Scholar
  57. 57.
    Zhu D, Hensel J, Hilgraf R, Abbasian M, Pornillos O, Deyanat-Yazdi G, Hua XH, Cox S (2010) Inhibition of protein kinase CK2 expression and activity blocks tumor cell growth. Mol Cell Biochem 333(1–2):159–167. doi: 10.1007/s11010-009-0216-0 CrossRefPubMedGoogle Scholar
  58. 58.
    Hamacher R, Saur D, Fritsch R, Reichert M, Schmid RM, Schneider G (2007) Casein kinase II inhibition induces apoptosis in pancreatic cancer cells. Oncol Rep 18(3):695–701PubMedGoogle Scholar
  59. 59.
    Piazza FA, Ruzzene M, Gurrieri C, Montini B, Bonanni L, Chioetto G, Di Maira G, Barbon F, Cabrelle A, Zambello R, Adami F, Trentin L, Pinna LA, Semenzato G (2006) Multiple myeloma cell survival relies on high activity of protein kinase CK2. Blood 108(5):1698–1707. doi: 10.1182/blood-2005-11-013672, blood-2005-11-013672 [pii]CrossRefPubMedGoogle Scholar
  60. 60.
    Yde CW, Frogne T, Lykkesfeldt AE, Fichtner I, Issinger OG, Stenvang J (2007) Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT. Cancer Lett 256(2):229–237. doi: 10.1016/j.canlet.2007.06.010, S0304-3835(07)00287-X [pii]CrossRefPubMedGoogle Scholar
  61. 61.
    Lawnicka H, Kowalewicz-Kulbat M, Sicinska P, Kazimierczuk Z, Grieb P, Stepien H (2010) Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro. Cell Tissue Res 340(2):371–379. doi: 10.1007/s00441-010-0960-1 CrossRefPubMedGoogle Scholar
  62. 62.
    Ruzzene M, Penzo D, Pinna LA (2002) Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem J 364(Pt 1):41–47PubMedCentralPubMedGoogle Scholar
  63. 63.
    Pagano MA, Meggio F, Ruzzene M, Andrzejewska M, Kazimierczuk Z, Pinna LA (2004) 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2. Biochem Biophys Res Commun 321(4):1040–1044. doi: 10.1016/j.bbrc.2004.07.067, S0006-291X(04)01549-9 [pii]CrossRefPubMedGoogle Scholar
  64. 64.
    Prudent R, Moucadel V, Lopez-Ramos M, Aci S, Laudet B, Mouawad L, Barette C, Einhorn J, Einhorn C, Denis JN, Bisson G, Schmidt F, Roy S, Lafanechere L, Florent JC, Cochet C (2008) Expanding the chemical diversity of CK2 inhibitors. Mol Cell Biochem 316(1–2):71–85. doi: 10.1007/s11010-008-9828-z CrossRefPubMedGoogle Scholar
  65. 65.
    Gianoncelli A, Cozza G, Orzeszko A, Meggio F, Kazimierczuk Z, Pinna LA (2009) Tetraiodobenzimidazoles are potent inhibitors of protein kinase CK2. Bioorg Med Chem 17(20):7281–7289. doi: 10.1016/j.bmc.2009.08.047 CrossRefPubMedGoogle Scholar
  66. 66.
    Lopez-Ramos M, Prudent R, Moucadel V, Sautel CF, Barette C, Lafanechere L, Mouawad L, Grierson D, Schmidt F, Florent JC, Filippakopoulos P, Bullock AN, Knapp S, Reiser JB, Cochet C (2010) New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights. FASEB J 24(9):3171–3185. doi: 10.1096/fj.09-143743, fj.09-143743 [pii]CrossRefPubMedGoogle Scholar
  67. 67.
    Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O’Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K (2010) CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 70(24):10288–10298. doi: 10.1158/0008-5472.can-10-1893 CrossRefPubMedGoogle Scholar
  68. 68.
    Manni S, Brancalion A, Tubi LQ, Colpo A, Pavan L, Cabrelle A, Ave E, Zaffino F, Di Maira G, Ruzzene M, Adami F, Zambello R, Pitari MR, Tassone P, Pinna LA, Gurrieri C, Semenzato G, Piazza F (2012) Protein kinase CK2 protects multiple myeloma cells from ER stress-induced apoptosis and from the cytotoxic effect of HSP90 inhibition through regulation of the unfolded protein response. Clin Cancer Res 18(7):1888–1900. doi: 10.1158/1078-0432.CCR-11-1789 CrossRefPubMedGoogle Scholar
  69. 69.
    Lin YC, Hung MS, Lin CK, Li JM, Lee KD, Li YC, Chen MF, Chen JK, Yang CT (2011) CK2 inhibitors enhance the radiosensitivity of human non-small cell lung cancer cells through inhibition of stat3 activation. Cancer Biother Radiopharm 26(3):381–388. doi: 10.1089/cbr.2010.0917 CrossRefPubMedGoogle Scholar
  70. 70.
    Gotz C, Gratz A, Kucklaender U, Jose J (2012) TF–a novel cell-permeable and selective inhibitor of human protein kinase CK2 induces apoptosis in the prostate cancer cell line LNCaP. Biochim Biophys Acta 1820(7):970–977. doi: 10.1016/j.bbagen.2012.02.009 CrossRefPubMedGoogle Scholar
  71. 71.
    Zhao M, Ma J, Zhu HY, Zhang XH, Du ZY, Xu YJ, Yu XD (2011) Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90. Mol Cancer 10:104. doi: 10.1186/1476-4598-10-104 CrossRefPubMedCentralPubMedGoogle Scholar
  72. 72.
    Yao K, Youn H, Gao X, Huang B, Zhou F, Li B, Han H (2012) Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells. Prostate 72(13):1423–1430. doi: 10.1002/pros.22493 CrossRefPubMedGoogle Scholar
  73. 73.
    Borgo C, Cesaro L, Salizzato V, Ruzzene M, Massimino ML, Pinna LA, Donella-Deana A (2013) Aberrant signalling by protein kinase CK2 in imatinib-resistant chronic myeloid leukaemia cells: biochemical evidence and therapeutic perspectives. Mol Oncol 7(6):1103–1115. doi: 10.1016/j.molonc.2013.08.006 CrossRefPubMedGoogle Scholar
  74. 74.
    Di Maira G, Brustolon F, Bertacchini J, Tosoni K, Marmiroli S, Pinna LA, Ruzzene M (2007) Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level. Oncogene 26(48):6915–6926. doi: 10.1038/sj.onc.1210495, 1210495 [pii]CrossRefPubMedGoogle Scholar
  75. 75.
    Sass G, Klinger N, Sirma H, Hashemolhosseini S, Hellerbrand C, Neureiter D, Wege H, Ocker M, Tiegs G (2011) Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT. Int J Oncol 39(2):433–442. doi: 10.3892/ijo.2011.1037 PubMedGoogle Scholar
  76. 76.
    Pierre F, Chua PC, O’Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, Michaux J, Nagasawa J, Schwaebe MK, Stefan E, Vialettes A, Whitten JP, Chen TK, Darjania L, Stansfield R, Bliesath J, Drygin D, Ho C, Omori M, Proffitt C, Streiner N, Rice WG, Ryckman DM, Anderes K (2011) Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer. Mol Cell Biochem 356(1–2):37–43. doi: 10.1007/s11010-011-0956-5 CrossRefPubMedGoogle Scholar
  77. 77.
    Prudent R, Moucadel V, Nguyen CH, Barette C, Schmidt F, Florent JC, Lafanechere L, Sautel CF, Duchemin-Pelletier E, Spreux E, Filhol O, Reiser JB, Cochet C (2010) Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. Cancer Res 70(23):9865–9874. doi: 10.1158/0008-5472.CAN-10-0917, 0008-5472.CAN-10-0917 [pii]CrossRefPubMedGoogle Scholar
  78. 78.
    Yoo JY, Lim BJ, Choi HK, Hong SW, Jang HS, Kim C, Chun KH, Choi KC, Yoon HG (2013) CK2-NCoR signaling cascade promotes prostate tumorigenesis. Oncotarget 4(7):972–983PubMedCentralPubMedGoogle Scholar
  79. 79.
    Bliesath J, Huser N, Omori M, Bunag D, Proffitt C, Streiner N, Ho C, Siddiqui-Jain A, O’Brien SE, Lim JK, Ryckman DM, Anderes K, Rice WG, Drygin D (2012) Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells. Cancer Lett 322(1):113–118. doi: 10.1016/j.canlet.2012.02.032 CrossRefPubMedGoogle Scholar
  80. 80.
    Siddiqui-Jain A, Bliesath J, Macalino D, Omori M, Huser N, Streiner N, Ho CB, Anderes K, Proffitt C, O’Brien SE, Lim JK, Von Hoff DD, Ryckman DM, Rice WG, Drygin D (2012) 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(4):994–1005. doi: 10.1158/1535-7163.MCT-11-0613 CrossRefPubMedGoogle Scholar
  81. 81.
    Marschke RF, Borad MJ, McFarland RW, Alvarez RH, Lim JK, Padgett CS, Von Hoff DD, O’Brien SE, Northfelt DW (2011) Findings from the phase I clinical trials of CX-4945, an orally bioavailable inhibitor of CK2. J Clin Oncol 29 (suppl):abstr 3087Google Scholar
  82. 82.
    Perera Y, Farina HG, Gil J, Rodriguez A, Benavent F, Castellanos L, Gomez RE, Acevedo BE, Alonso DF, Perea SE (2009) 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(5):1189–1196. doi: 10.1158/1535-7163.MCT-08-1056, 1535-7163.MCT-08-1056 [pii]CrossRefPubMedGoogle Scholar
  83. 83.
    Perea SE, Reyes O, Puchades Y, Mendoza O, Vispo NS, Torrens I, Santos A, Silva R, Acevedo B, Lopez E, Falcon V, Alonso DF (2004) Antitumor effect of a novel proapoptotic peptide that impairs the phosphorylation by the protein kinase 2 (casein kinase 2). Cancer Res 64(19):7127–7129. doi: 10.1158/0008-5472.CAN-04-2086, 64/19/7127 [pii]CrossRefPubMedGoogle Scholar
  84. 84.
    Perera Y, Farina HG, Hernandez I, Mendoza O, Serrano JM, Reyes O, Gomez DE, Gomez RE, Acevedo BE, Alonso DF, Perea SE (2008) Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in mice. Int J Cancer 122(1):57–62. doi: 10.1002/ijc.23013 CrossRefPubMedGoogle Scholar
  85. 85.
    Martins LR, Perera Y, Lucio P, Silva MG, Perea SE, Barata JT (2014) Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specific cell-permeable peptide inhibitor. Oncotarget 5(1):258–263PubMedCentralPubMedGoogle Scholar
  86. 86.
    Perea SE, Baladron I, Garcia Y, Perera Y, Lopez A, Soriano JL, Batista N, Palau A, Hernandez I, Farina H, Garcia I, Gonzalez L, Gil J, Rodriguez A, Solares M, Santana A, Cruz M, Lopez M, Valenzuela C, Reyes O, Lopez-Saura PA, Gonzalez CA, Diaz A, Castellanos L, Sanchez A, Betancourt L, Besada V, Gonzalez LJ, Garay H, Gomez R, Gomez DE, Alonso DF, Perrin P, Renualt JY, Sigman H, Herrera L, Acevedo B (2011) CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research. Mol Cell Biochem 356(1–2):45–50. doi: 10.1007/s11010-011-0950-y CrossRefPubMedGoogle Scholar
  87. 87.
    Solares AM, Santana A, Baladron I, Valenzuela C, Gonzalez CA, Diaz A, Castillo D, Ramos T, Gomez R, Alonso DF, Herrera L, Sigman H, Perea SE, Acevedo BE, Lopez-Saura P (2009) 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 9:146. doi: 10.1186/1471-2407-9-146 CrossRefPubMedCentralPubMedGoogle Scholar
  88. 88.
    Unger GM, Kren BT, Korman VL, Kimbrough TG, Vogel RI, Ondrey FG, Trembley JH, Ahmed K (2014) Mechanism and efficacy of sub-50 nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma. Mol Cancer Ther 13(8):2018–2029CrossRefPubMedGoogle Scholar
  89. 89.
    Aukhil I, Joshi P, Yan Y, Erickson HP (1993) Cell- and heparin-binding domains of the hexabrachion arm identified by tenascin expression proteins. J Biol Chem 268(4):2542–2553PubMedGoogle Scholar
  90. 90.
    Erickson HP, Bourdon MA (1989) Tenascin: an extracellular matrix protein prominent in specialized embryonic tissues and tumors. Annu Rev Cell Biol 5:71–92. doi: 10.1146/annurev.cb.05.110189.000443 CrossRefPubMedGoogle Scholar
  91. 91.
    Yokoyama K, Erickson HP, Ikeda Y, Takada Y (2000) Identification of amino acid sequences in fibrinogen gamma-chain and tenascin C C-terminal domains critical for binding to integrin alpha vbeta 3. J Biol Chem 275(22):16891–16898. doi: 10.1074/jbc.M000610200, M000610200 [pii]CrossRefPubMedGoogle Scholar
  92. 92.
    Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10(1):9–22. doi: 10.1038/nrc2748 CrossRefPubMedGoogle Scholar
  93. 93.
    Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massague J (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17(7):867–874. doi: 10.1038/nm.2379 CrossRefPubMedCentralPubMedGoogle Scholar
  94. 94.
    Van Obberghen-Schilling E, Tucker RP, Saupe F, Gasser I, Cseh B, Orend G (2011) Fibronectin and tenascin-C: accomplices in vascular morphogenesis during development and tumor growth. Int J Dev Biol 55(4–5):511–525. doi: 10.1387/ijdb.103243eo CrossRefPubMedGoogle Scholar
  95. 95.
    Midwood KS, Orend G (2009) The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal 3(3–4):287–310. doi: 10.1007/s12079-009-0075-1 CrossRefPubMedCentralPubMedGoogle Scholar
  96. 96.
    Trembley JH, Unger GM, Cespedes Gomez O, Abedin MJ, Korman VL, Vogel RI, Niehans G, Kren BT, Ahmed K (2014) Tenfibgen-DMAT nanocapsule delivers CK2 inhibitor DMAT to prostate cancer xenograft tumors causing inhibition of cell proliferation. Mol Cell Pharmacol 6:15–25Google Scholar
  97. 97.
    Trembley JH, Unger GM, Korman VL, Abedin MJ, Nacusi LP, Vogel RI, Slaton JW, Kren BT, Ahmed K (2014) Tenfibgen ligand nanoencapsulation delivers bi-functional anti-CK2 RNAi oligomer to key sites for prostate cancer targeting. PLoS One. doi: 10.1371/journal.pone.0109970 PubMedCentralPubMedGoogle Scholar
  98. 98.
    Slaton JW, Unger GM, Sloper DT, Davis AT, Ahmed K (2004) Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model. Mol Cancer Res 2(12):712–721PubMedGoogle Scholar
  99. 99.
    Tousignant JD, Gates AL, Ingram LA, Johnson CL, Nietupski JB, Cheng SH, Eastman SJ, Scheule RK (2000) Comprehensive acute toxicities induced by systemic administration of cationic lipid:plasmid DNA complexes in mice. Hum Gene Ther 11:2493–2513CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Khalil Ahmed
    • 1
  • Gretchen Unger
    • 2
  • Betsy T. Kren
    • 3
    • 4
    • 5
    • 6
  • Janeen H. Trembley
    • 3
    • 4
    • 5
    • 6
    Email author
  1. 1.Department of Laboratory Medicine and PathologyUniversity of Minnesota Medical School and Minneapolis VA Health Care SystemMinneapolisUSA
  2. 2.GeneSegues, Inc.ChaskaUSA
  3. 3.Cellular and Molecular Biochemistry Research Laboratory (151), Minneapolis Veterans Affairs Health Care SystemMinneapolisUSA
  4. 4.Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisUSA
  5. 5.Masonic Cancer Center, University of MinnesotaMinneapolisUSA
  6. 6.Cellular and Molecular Biochemistry Research Laboratory (151), Veterans Affairs Medical CenterMinneapolisUSA

Personalised recommendations