Antisense oligonucleotide inhibition of serine/threonine kinases: an innovative approach to cancer treatment.

The identification of genes that confer a growth advantage on neoplastic cells and the understanding of the genetic mechanism(s) responsible for their activation have made possible a direct genetic approach to cancer treatment using nucleic acid therapeutics. Moreover, the ability to block the expression of individual genes that promote carcinogenesis provides a powerful tool to explore the molecular basis of normal growth regulation, as well as the opportunity for therapeutic intervention. One technique for turning off a single activated gene is the use of antisense oligodeoxynucleotides and their analogs for inhibition of gene expression. The serine/threonine kinases are involved in mediating intracellular responses to external signals, such as growth factors, hormones, and neurotransmitters, and are involved in cell proliferation and oncogenesis. Described herein are recent studies supporting the potential use of oligonucleotides targeting these kinases as chemotherapeutic agents for cancer treatment. The serine/threonine kinases included here are protein kinase A, protein kinase C, and c-raf-1 kinase.

[1]  B. Paterson,et al.  Structural gene identification and mapping by DNA-mRNA hybrid-arrested cell-free translation. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Malkinson,et al.  Cyclic AMP-dependent protein kinases from normal and SV40-transformed 3T3 cells , 1976, Nature.

[3]  Z. Darżynkiewicz,et al.  Expression of cyclins-B and cyclins-e in individual molt-4 cells and in stimulated human-lymphocytes during their progression through the cell-cycle. , 1993, International journal of oncology.

[4]  F. Levy,et al.  Molecular cloning, complementary deoxyribonucleic acid structure and predicted full-length amino acid sequence of the hormone-inducible regulatory subunit of 3'-5'-cyclic adenosine monophosphate-dependent protein kinase from human testis. , 1988, Molecular endocrinology.

[5]  G. Tortora,et al.  Differentiation of HL-60 leukemia by type I regulatory subunit antisense oligodeoxynucleotide of cAMP-dependent protein kinase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[6]  B. Dolnick.  Antisense agents in cancer research and therapeutics. , 1991, Cancer investigation.

[7]  C. Grillo,et al.  Subcellular distribution of cyclic adenosine 3',5'-monophosphate-binding protein and estrogen receptors in control pituitaries and estrogen-induced pituitary tumors. , 1990, Journal of the National Cancer Institute.

[8]  Y. Cho‐Chung,et al.  Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa. , 1994, British Journal of Cancer.

[9]  M. Grever,et al.  Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. , 1994, Molecular pharmacology.

[10]  Y. Cho‐Chung.  Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. , 1990, Cancer research.

[11]  E. Lesnik,et al.  Enhanced activity of an antisense oligonucleotide targeting murine protein kinase C-alpha by the incorporation of 2'-O-propyl modifications. , 1996, Nucleic acids research.

[12]  J. Bos,et al.  The ras gene family and human carcinogenesis. , 1988, Mutation research.

[13]  Susan S. Taylor,et al.  cAMP‐dependent protein kinase: prototype for a family of enzymes , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  S. Yuspa.  The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis--thirty-third G. H. A. Clowes Memorial Award Lecture. , 1994, Cancer research.

[15]  Y. Nishizuka,et al.  Protein kinase C, calcium and phospholipid degradation. , 1992, Trends in biochemical sciences.

[16]  A. Ullrich,et al.  Down-regulation of protein kinase C is due to an increased rate of degradation. , 1987, The Biochemical journal.

[17]  U. Eppenberger,et al.  Altered cellular ratio of type I and type II cyclic AMP‐dependent protein kinase in human mammary tumors , 1979, FEBS letters.

[18]  A. Malkinson,et al.  Cyclic AMP‐dependent protein kinases from Balb 3T3 cells and other 3T3 derived lines , 1981, Journal of cellular physiology.

[19]  L. Neckers,et al.  Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway , 1996, Molecular and cellular biology.

[20]  P. D. Cook,et al.  Evaluation of 2'-modified oligonucleotides containing 2'-deoxy gaps as antisense inhibitors of gene expression. , 1993, The Journal of biological chemistry.

[21]  S. Freier,et al.  Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. , 1991, The Journal of biological chemistry.

[22]  S. Crooke.  Therapeutic applications of oligonucleotides. , 1992, Bio/technology.

[23]  G. Trainor,et al.  Potent antisense oligonucleotides to the human multidrug resistance-1 mRNA are rationally selected by mapping RNA-accessible sites with oligonucleotide libraries. , 1996, Nucleic acids research.

[24]  A. Basu,et al.  The potential of protein kinase C as a target for anticancer treatment. , 1993, Pharmacology & therapeutics.

[25]  Russell Dh.  Type I cyclic AMP-dependent protein kinase as a positive effector of growth. , 1978 .

[26]  E. Wickstrom,et al.  Walking along human c-myc mRNA with antisense oligodeoxynucleotides: maximum efficacy at the 5' cap region. , 1991, Oncogene research.

[27]  R. Glazer,et al.  8-chloroadenosine 3',5'-monophosphate as a novel modulator of multidrug-resistance. , 1993, International journal of oncology.

[28]  T. Yamamoto,et al.  Detection of a raf-related and two other transforming DNA sequences in human tumors maintained in nude mice. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. Iversen.  In vivo studies with phosphorothioate oligonucleotides: pharmacokinetics prologue. , 1991, Anti-cancer drug design.

[30]  D. Ecker,et al.  Pharmacology of antisense therapeutic agents : cancer and inflamination. , 1996, Methods in molecular medicine.

[31]  J. Troppmair,et al.  The ins and outs of Raf kinases. , 1994, Trends in biochemical sciences.

[32]  Y. Cho‐Chung,et al.  Anticarcinogenic effect of N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate on 7,12-dimethylbenz(a)anthracene mammary tumor induction in the rat and its relationship to cyclic adenosine 3':5'-monophosphate metabolism and protein kinase. , 1983, Cancer research.

[33]  M. Inouye,et al.  A unique mechanism regulating gene expression: translational inhibition by a complementary RNA transcript (micRNA). , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Cech,et al.  Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 2. Kinetic description of the reaction of an RNA substrate that forms a mismatch at the active site. , 1990, Biochemistry.

[35]  Y. Cho‐Chung,et al.  Antisense-protein kinase A: a single-gene-based therapeutic approach. , 1997, Antisense & nucleic acid drug development.

[36]  P. Tagliaferri,et al.  Induction of megakaryocytic differentiation and modulation of protein kinase gene expression by site-selective cAMP analogs in K-562 human leukemic cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[37]  U. Walter,et al.  Regulation of the cellular and subcellular concentrations and distribution of cyclic nucleotide-dependent protein kinases. , 1984, Advances in cyclic nucleotide and protein phosphorylation research.

[38]  G. Tortora,et al.  An antisense oligodeoxynucleotide that depletes RI alpha subunit of cyclic AMP-dependent protein kinase induces growth inhibition in human cancer cells. , 1993, Cancer research.

[39]  G. Tortora,et al.  An antisense oligodeoxynucleotide targeted against the type II beta regulatory subunit mRNA of protein kinase inhibits cAMP-induced differentiation in HL-60 leukemia cells without affecting phorbol ester effects. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[41]  C. Hélène,et al.  Antisense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell proliferation and tumorigenicity in nude mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  P. Tagliaferri,et al.  Reverse transformation of Harvey murine sarcoma virus-transformed NIH/3T3 cells by site-selective cyclic AMP analogs. , 1988, The Journal of biological chemistry.

[43]  N. Yamamoto,et al.  Inhibition of human immunodeficiency virus (HIV-1) replication by synthetic oligo-RNA derivatives. , 1989, Nucleic acids research.

[44]  J. Lisziewicz,et al.  Study of antisense oligonucleotide phosphorothioates containing segments of oligodeoxynucleotides and 2′-o- methyloligoribonucleotides , 1994 .

[45]  E. Lesnik,et al.  Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C-raf kinase supports an antisense mechanism of action in vivo. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. Sugimura,et al.  Molecular cloning of an activated human oncogene, homologous to v-raf, from primary stomach cancer. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Martuza,et al.  Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide. , 1996, Molecular pharmacology.

[48]  D. Salomon,et al.  Site‐selective 8‐chloroadenosine 3′,5′‐cyclic monophosphate inhibits transformation and transforming growth factor α production in Ki‐ras‐transformed rat fibroblasts , 1989, FEBS letters.

[49]  C. Rubin,et al.  Identification and differential expression of two forms of regulatory subunits (RII) of cAMP-dependent protein kinase II in Friend erythroleukemic cells. Differentiation and 8-bromo-cAMP elicit a large and selective increase in the rate of biosynthesis of only one type of RII. , 1985, The Journal of biological chemistry.

[50]  M. Boyd,et al.  Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen , 1995 .

[51]  O. Uhlenbeck.  Complementary oligonucleotide binding to transfer RNA. , 1972, Journal of molecular biology.

[52]  L. Miraglia,et al.  Inhibition of Growth of Human Tumor Cell Lines in Nude Mice by an Antisense Oligonucleotide Inhibitor of Protein Kinase C-α Expression , 1996 .

[53]  G. Tortora,et al.  Down‐regulation of riα subunit of camp‐dependent protein kinase induces growth inhibition of human mammary epithelial cells transformed by c‐ha‐ras and c‐erbb‐2 proto‐oncogenes , 1993, International journal of cancer.

[54]  J. Wands,et al.  Specific inhibition of hepatitis C virus expression by antisense oligodeoxynucleotides. In vitro model for selection of target sequence. , 1994, The Journal of biological chemistry.

[55]  S. Yuspa,et al.  The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. , 1998, Journal of dermatological science.

[56]  C. Borner,et al.  Continuous synthesis of two protein-kinase-C-related proteins after down-regulation by phorbol esters. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Uhler,et al.  Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. , 1988, Recent progress in hormone research.

[58]  W. Yasui,et al.  Effect of gastrin on gastric mucosal cyclic adenosine 3':5'-monophosphate-dependent protein kinase activity in rat stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine. , 1985, Cancer research.

[59]  R. Maurer,et al.  A cloned bovine cDNA encodes an alternate form of the catalytic subunit of cAMP-dependent protein kinase. , 1986, The Journal of biological chemistry.

[60]  E. Nishida,et al.  The MAP kinase cascade is essential for diverse signal transduction pathways. , 1993, Trends in biochemical sciences.

[61]  S. Døskeland,et al.  Protein kinases in human renal cell carcinoma and renal cortex. A comparison of isozyme distribution and of responsiveness to adenosine 3':5'-cyclic monophosphate. , 1978, Archives of biochemistry and biophysics.

[62]  Yun‐Sil Lee,et al.  Definition by specific antisense oligonucleotides of a role for protein kinase Cα in expression of differentiation markers in normal and neoplastic mouse epidermal keratinocytes , 1997, Molecular carcinogenesis.

[63]  N. Dean,et al.  Inhibition of protein kinase C-alpha expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[64]  L. Dekker,et al.  Protein kinase C--a question of specificity. , 1994, Trends in biochemical sciences.

[65]  G. Tortora,et al.  8-Chloro-cAMP inhibits transforming growth factor alpha transformation of mammary epithelial cells by restoration of the normal mRNA patterns for cAMP-dependent protein kinase regulatory subunit isoforms which show disruption upon transformation. , 1990, The Journal of biological chemistry.

[66]  N. Ledinko,et al.  Increase in type I cyclic adenosine 3':5'-monophosphate-dependent protein kinase activity and specific accumulation of type I regulatory subunits in adenovirus type 12-transformed cells. , 1984, Cancer Research.

[67]  S. Freier,et al.  The binding of complementary oligoribonucleotides to yeast initiator Transfer RNA. , 1975, Biochemistry.

[68]  R. Elton,et al.  Types of cyclic AMP binding proteins in human breast cancers. , 1993, European journal of cancer.

[69]  Doriano Fabbro,et al.  Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase , 1996, Nature Medicine.

[70]  Y. Nishizuka.  Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. , 1992, Science.

[71]  E. Wickstrom.  Prospects for antisense nucleic acid therapy of cancer and AIDS , 1991 .

[72]  S. Beebe,et al.  Molecular cloning of a tissue-specific protein kinase (C gamma) from human testis--representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. , 1990, Molecular endocrinology.

[73]  N. Dean,et al.  Inhibition of protein kinase C-alpha expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. , 1994, The Journal of biological chemistry.

[74]  Cyclic Nucleotide-Dependent Protein Kinases , 2000 .

[75]  G. Merlo,et al.  Retroviral vector-mediated overexpression of the RII beta subunit of the cAMP-dependent protein kinase induces differentiation in human leukemia cells and reverts the transformed phenotype of mouse fibroblasts. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[76]  D. Ecker,et al.  Implication of RNA structure on antisense oligonucleotide hybridization kinetics. , 1992, Biochemistry.

[77]  W. Miller,et al.  Tumour cyclic AMP binding proteins and endocrine responsiveness in patients with inoperable breast cancer. , 1987, British Journal of Cancer.

[78]  Y. Cho‐Chung,et al.  Overexpresson of RIIβ, Regulatory Subunit of Protein Kinase A in Human Colon Carcinoma Cell Induces Growth Arrest and Phenotypic Changes that are Abolished by Site‐Directed Mutation of RIIβ , 1996 .

[79]  S. Freier,et al.  Second Generation of Antisense Oligonucleotides: From Nuclease Resistance to Biological Efficacy in Animals , 1996, CHIMIA.

[80]  Y. Cho‐Chung,et al.  A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth , 1995, Nature Medicine.

[81]  G. Tortora,et al.  Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[82]  T. Martin,et al.  Selective hormonal activation of cyclic AMP-dependent protein kinase isoenzymes in normal and malignant osteoblasts. , 1982, The Journal of biological chemistry.

[83]  A. Green,et al.  Distribution and properties of type I and type II binding proteins in the cyclic adenosine 3':5'-monophosphate-dependent protein kinase system in Wilms' tumor. , 1984, Cancer research.

[84]  J. Cleveland,et al.  Oncogenes: clinical relevance. , 1987, Haematology and blood transfusion.

[85]  E. Krebs,et al.  Phosphorylation-dephosphorylation of enzymes. , 1979, Annual review of biochemistry.