Antisense therapy of prostate carcinoma by targeting protein kinase CK2

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Protein kinase CK2 (formerly casein kinase 2 or II) plays vital roles in cell growth, proliferation, and suppression of apoptosis (Ahmed et al., Trends in Cell Biol 12: 226-230, 2002). While the role of CK2 in cell growth and proliferation is well studied, we have recently shown that CK2 potently suppresses apoptosis mediated by diverse agents such as etoposide, heat shock, removal of survival factors, and death receptors. Cancer cell phenotype is characterized by dysregulation of both proliferation and apoptosis. Overexpression of CK2 in cancer cells may therefore not only promote proliferation but also suppress apoptosis. These characteristics of CK2 provide the impetus for investigation of its potential as a therapeutic target. We have previously shown that antisense CK2α ODN can potently induce apoptosis in cancer cells in culture. Here we report the effects of antisense CK2α ODN delivered by different routes into prostate tumor xenografts. Prostate cancer xenograft in nude mice was generated using PC3-LN4 cells injected into the subcutis of mice. Intratumoral injection of the antisense CK2α ODN resulted in eradication of prostate cancer tumors in vivo in a dose and time dependent manner. An analysis of the tumors treated with antisense CK2α ODN demonstrated a downregulation of CK2 message and nuclear-associated activity. Under similar experimental conditions, the normal cells and tissue were relatively resistant to the effect of antisense CK2α ODN with evidence of minimal apoptosis. We also show data that delivery of naked antisense CK2α ODN (phosphorothioate form) by the intravenous route in nude mice carrying the orthotopic PC3-LN4 tumor can also effectively downregulate CK2 resulting in induction of apoptosis in the tumor. To develop approaches for specific and uniform delivery of the antisense to tumors in vivo we have utilized antisense CK2α ODN (phosphodiester form) encapsulated in sub-50 nm tenascin nanocapsules. When delivered via the intravenous route these formulations were found to be significantly more effective than the naked antisense ODN. Together, these data further support the notion that CK2 is a promising target for anticancer therapy, and that use of formulated antisense ODN for downregulation of CK2 merits consideration. [Supported by N.C.I. and V.A. Medical Research funds].