Classical PKC isoforms in cancer

Pharmacological Research

Volumn 55, Issue 6, 2007, Pages 477-486

  Martiny Baron, Georg ^a   Fabbro, Doriano ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Cancer; PKC inhibitors; Protein kinase C

Indexed keywords

12 (2 CYANOETHYL) 6,7,12,13 TETRAHYDRO 13 METHYL 5 OXOINDOLO[2,3 A]PYRROLO[3,4 C]CARBAZOLE; 2 [1 (3 AMIDINOTHIOPROPYL) 1H INDOL 3 YL] 3 (1 METHYL 1H INDOL 3 YL)MALEIMIDE; 7 HYDROXYSTAUROSPORINE; BRYOSTATIN 1; CARBOPLATIN; CEP 701; CYTOTOXIC AGENT; DOXORUBICIN; ENZASTAURIN; GEMCITABINE; IMATINIB; ISIS 3521; MIDOSTAURIN; MILTEFOSINE; PACLITAXEL; PROTEIN KINASE C; PROTEIN KINASE C ALPHA; PROTEIN KINASE C BETA; PROTEIN KINASE C BETA INHIBITOR; PROTEIN KINASE C GAMMA; PROTEIN KINASE C INHIBITOR; PROTEIN SERINE THREONINE KINASE; QUERCETIN; RUBOXISTAURIN; SAFINGOL; TAMOXIFEN;

ACUTE GRANULOCYTIC LEUKEMIA; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; B CELL LYMPHOMA; BASAL CELL CARCINOMA; BLADDER CANCER; BREAST CANCER; CALCIUM SIGNALING; CANCER THERAPY; CARCINOGENESIS; CELL DIFFERENTIATION; CELL TRANSFORMATION; CHROMATURIA; CLINICAL TRIAL; COLON CANCER; COMBINATION CHEMOTHERAPY; DIABETIC ANGIOPATHY; DIABETIC NEPHROPATHY; DIABETIC NEUROPATHY; DIABETIC RETINOPATHY; DRUG TARGETING; DRUG WITHDRAWAL; ENDOMETRIUM CANCER; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME MECHANISM; ENZYME REGULATION; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; GASTROINTESTINAL TOXICITY; GENE MUTATION; GLIOMA; HEMATOLOGIC MALIGNANCY; HUMAN; LIVER CELL CARCINOMA; LIVER TOXICITY; LUNG NON SMALL CELL CANCER; LYMPHOCYTOPENIA; LYMPHOMA; MELANOMA; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; MYALGIA; MYELOPROLIFERATIVE DISORDER; NONHODGKIN LYMPHOMA; NONHUMAN; ONCOGENE; OVARY CANCER; PHLEBITIS; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FAMILY; QT PROLONGATION; URINE COMPOSITION DISORDER;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEOPLASMS; OLIGONUCLEOTIDES; PROTEIN KINASE C; PROTEIN KINASE C-ALPHA; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 34250703569     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2007.04.001     Document Type: Article

References (152)

1. van Rossum R.L., Patterson D.B., Nikolaidis N., Gilland D.L., and Snyder S.H. Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling. Trends Biochem Sci 30 (2005) 688-697
2. Mellorand H., and Parker P.J. The extended protein kinase C superfamily. Biochem J 332 Pt 2 (1998) 281-292
3. Way K.J., Chouand E., and King G.L. Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends Pharmacol Sci 21 (2000) 181-187
4. Hugand H., and Sarre T.F. Protein kinase C isoenzymes: divergence in signal transduction?. Biochem J 291 Pt 2 (1993) 329-343
5. Pears C.J., Kour G., Kempand C., House B.E., and Parker P.J. Mutagenesis of the pseudosubstrate site of protein kinase C leads to activation. Eur J Biochem 194 (1990) 89-94
6. Parekh D.B., Ziegler W., and Parker P.J. Multiple pathways control protein kinase C phosphorylation. Embo J 19 (2000) 496-503
7. Parkerand P.J., and Murray-Rust J. PKC at a glance. J Cell Sci 117 (2004) 131-132
8. Rhee S.G. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70 (2001) 281-312
9. Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawaand U., and Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257 (1982) 7847-7851
10. Niedel J.E., Kuhnand L.J., and Vandenbark G.R. Phorbol diester receptor copurifies with protein kinase C. Proc Natl Acad Sci USA 80 (1983) 36-40
11. Dale I.L., Bradshaw T.D., Gescherand A., and Pettit G.R. Comparison of effects of bryostatins 1 and 2 and 12-O-tetradecanoylphorbol-13-acetate on protein kinase C activity in A549 human lung carcinoma cells. Cancer Res 49 (1989) 3242-3245
12. Kennedy M.J., Prestigiacomo L.J., Tyler G., Mayand W.S., and Davidson N.E. Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res 52 (1992) 1278-1283
13. Gschwendt M., Kittstein W., Lindnerand D., and Marks F. Differential inhibition by staurosporine of phorbol ester, bryostatin and okadaic acid effects on mouse skin. Cancer Lett 66 (1992) 139-146
14. Blumberg P.M. Complexities of the protein kinase C pathway. Mol Carcinog 4 (1991) 339-344
15. Nakashima S. Protein kinase C alpha (PKC alpha): regulation and biological function. J Biochem (Tokyo) 132 (2002) 669-675
16. Koivunen J., Aaltonen V., Koskela S., Lehenkari P., Laatoand M., and Peltonen J. Protein kinase C alpha/beta inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells. Cancer Res 64 (2004) 5693-5701
17. Masur K., Lang K., Niggemann B., Zanker K.S., and Entschladen F. High PKC alpha and low E-cadherin expression contribute to high migratory activity of colon carcinoma cells. Mol Biol Cell 12 (2001) 1973-1982
18. Engers R., Mrzyk S., Springer E., Fabbro D., Weissgerber G., Gernharzand C.D., et al. Protein kinase C in human renal cell carcinomas: role in invasion and differential isoenzyme expression. Br J Cancer 82 (2000) 1063-1069
19. Parsons M., Keppler M.D., Kline A., Messent A., Humphries M.J., Gilchrist R., et al. Site-directed perturbation of protein kinase C-integrin interaction blocks carcinoma cell chemotaxis. Mol Cell Biol 22 (2002) 5897-5911
20. Podar K., Tai Y.T., Lin B.K., Narsimhan R.P., Sattler M., Kijima T., et al. Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation. J Biol Chem 277 (2002) 7875-7881
21. Osterand H., and Leitges M. Protein kinase C alpha but not PKCzeta suppresses intestinal tumor formation in ApcMin/+ mice. Cancer Res 66 (2006) 6955-6963
22. Langzam L., Koren R., Gal R., Kugel V., Paz A., Farkas A., et al. Patterns of protein kinase C isoenzyme expression in transitional cell carcinoma of bladder. Relation to degree of malignancy. Am J Clin Pathol 116 (2001) 377-385
23. Varga A., Czifra G., Tallai B., Nemeth T., Kovacs I., Kovacsand L., et al. Tumor grade-dependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas. Eur Urol 46 (2004) 462-465
24. Koren R., Ben Meir D., Langzam L., Dekel Y., Konichezky M., Baniel J., et al. Expression of protein kinase C isoenzymes in benign hyperplasia and carcinoma of prostate. Oncol Rep 11 (2004) 321-326
25. Koren R., Langzam L., Paz A., Livne P.M., Galand R., and Sampson S.R. Protein kinase C (PKC) isoenzymes immunohistochemistry in lymph node revealing solution-fixed, paraffin-embedded bladder tumors. Appl Immunohistochem Mol Morphol 8 (2000) 166-171
26. Fournier D.B., Chisamore M., Lurain J.R., Rademaker A.W., Jordan V.C., and Tonetti D.A. Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: possible role in AP-1-mediated proliferation of ER-negative endometrial cancer. Gynecol Oncol 81 (2001) 366-372
27. Tsai J.H., Tsai M.T., Su W.W., Chen Y.L., Wu T.T., Hsieh Y.S., et al. Expression of protein kinase C alpha in biopsies and surgical specimens of human hepatocellular carcinoma. Chin J Physiol 48 (2005) 139-143
28. Lahn M., Sundell K., and Kohler G. The role of protein kinase C-alpha in hematologic malignancies. Acta Haematol 115 (2006) 1-8
29. Neill G.W., Ghali L.R., Green J.L., Ikram M.S., Philpott M.P., and Quinn A.G. Loss of protein kinase C alpha expression may enhance the tumorigenic potential of Gli1 in basal cell carcinoma. Cancer Res 63 (2003) 4692-4697
30. Kahl-Rainer P., Karner-Hanusch J., Weiss W., and Marian B. Five of six protein kinase C isoenzymes present in normal mucosa show reduced protein levels during tumor development in the human colon. Carcinogenesis 15 (1994) 779-782
31. Gokmen-Polar Y., Murray N.R., Velasco M.A., Gatalica Z., and Fields A.P. Elevated protein kinase C betaII is an early promotive event in colon carcinogenesis. Cancer Res 61 (2001) 1375-1381
32. Ng T., Squire A., Hansra G., Bornancin F., Prevostel C., Hanby A., et al. Imaging protein kinase C alpha activation in cells. Science 283 (1999) 2085-2089
33. Kerfoot C., Huang W., and Rotenberg S.A. Immunohistochemical analysis of advanced human breast carcinomas reveals downregulation of protein kinase C alpha. J Histochem Cytochem 52 (2004) 419-422
34. Ainsworth P.D., Winstanley J.H., Pearson J.M., Bishopand H.M., and Garrod D.R. Protein kinase C alpha expression in normal breast, ductal carcinoma in situ and invasive ductal carcinoma. Eur J Cancer 40 (2004) 2269-2273
35. Ways D.K., Kukoly C.A., deVente J., Hooker J.L., Bryant W.O., Posekany K.J., et al. MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. J Clin Invest 95 (1995) 1906-1915
36. Lahn M., Kohler G., Sundell K., Su C., Li S., Paterson B.M., et al. Protein kinase C alpha expression in breast and ovarian cancer. Oncology 67 (2004) 1-10
37. Tan M., Li P., Sun M., Yinand G., and Yu D. Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors. Oncogene 25 (2006) 3286-3295
38. Martiny-Baron G., Kazanietz M.G., Mischak H., Blumberg P.M., Kochs G., Hug H., et al. Selective inhibition of protein kinase C isozymes by the indolocarbazole Go 6976. J Biol Chem 268 (1993) 9194-9197
39. Leitges M., Schmedt C., Guinamard R., Davoust J., Schaal S., Stabel S., et al. Immunodeficiency in protein kinase cbeta-deficient mice. Science 273 (1996) 788-791
40. Suzuma K., Takahara N., Suzuma I., Isshiki K., Ueki K., Leitges M., et al. Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. Proc Natl Acad Sci USA 99 (2002) 721-726
41. Avignon A., and Sultan A. PKC-B inhibition: a new therapeutic approach for diabetic complications?. Diabetes Metab 32 (2006) 205-213
42. Zhang J., Anastasiadis P.Z., Liu Y., Thompson E.A., and Fields A.P. Protein kinase C (PKC) betaII induces cell invasion through a Ras/Mek-, PKC iota/Rac 1-dependent signaling pathway. J Biol Chem 279 (2004) 22118-22123
43. Graff J.R., McNulty A.M., Hanna K.R., Konicek B.W., Lynch R.L., Bailey S.N., et al. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65 (2005) 7462-7469
44. Wang Q., Zhou Y., and Evers B.M. Neurotensin phosphorylates GSK-3alpha/beta through the activation of PKC in human colon cancer cells. Neoplasia 8 (2006) 781-787
45. Shipp M.A., Ross K.N., Tamayo P., Weng A.P., Kutok J.L., Aguiar R.C., et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8 (2002) 68-74
46. Gilhooly E.M., Morse-Gaudio M., Bianchi L., Reinhart L., Rose D.P., Connolly J.M., et al. Loss of expression of protein kinase C beta is a common phenomenon in human malignant melanoma: a result of transformation or differentiation?. Melanoma Res 11 (2001) 355-369
47. Krasagakis K., Fimmel S., Genten D., Eberle J., Quas P., Ziegler W., et al. Lack of protein kinase C (PKC)-beta and low PKC-alpha, -delta, -epsilon, and -zeta isozyme levels in proliferating human melanoma cells. Int J Oncol 20 (2002) 865-871
48. Abeliovich A., Chen C., Goda Y., Silva A.J., Stevens C.F., and Tonegawa S. Modified hippocampal long-term potentiation in PKC gamma-mutant mice. Cell 75 (1993) 1253-1262
49. Tonegawa S., Li Y., Erzurumlu R.S., Jhaveri S., Chen C., Goda Y., et al. The gene knockout technology for the analysis of learning and memory, and neural development. Prog Brain Res 105 (1995) 3-14
50. Malmberg A.B., Chen C., Tonegawa S., and Basbaum A.I. Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma. Science 278 (1997) 279-283
51. Mazzoni E., Adam A., Bal de Kier Joffe E., and Aguirre-Ghiso J.A. Immortalized mammary epithelial cells overexpressing protein kinase C gamma acquire a malignant phenotype and become tumorigenic in vivo. Mol Cancer Res 1 (2003) 776-787
52. Kamimura K., Hojoand H., and Abe M. Characterization of expression of protein kinase C isozymes in human B-cell lymphoma: relationship between its expression and prognosis. Pathol Int 54 (2004) 224-230
53. Takahashi I., Kobayashi E., Asano K., Yoshida M., and Nakano H. UCN-01, a selective inhibitor of protein kinase C from Streptomyces. J Antibiot (Tokyo) 40 (1987) 1782-1784
54. Akiyama T., Yoshida T., Tsujita T., Shimizu M., Mizukami T., Okabe M., et al. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 57 (1997) 1495-1501
55. Akiyama T., Sugiyama K., Shimizu M., Tamaoki T., and Akinaga S. G1-checkpoint function including a cyclin-dependent kinase 2 regulatory pathway as potential determinant of 7-hydroxystaurosporine (UCN-01)-induced apoptosis and G1-phase accumulation. Jpn J Cancer Res 90 (1999) 1364-1372
56. Wang Q., Worland P.J., Clark J.L., Carlson B.A., and Sausville E.A. Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Differ 6 (1995) 927-936
57. Shao R.G., Cao C.X., Shimizu T., O'Connor P.M., Kohn K.W., and Pommier Y. Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53 function. Cancer Res 57 (1997) 4029-4035
58. Nieves-Neira W., and Pommier Y. Apoptotic response to camptothecin and 7-hydroxystaurosporine (UCN-01) in the 8 human breast cancer cell lines of the NCI anticancer drug screen: multifactorial relationships with topoisomerase I, protein kinase C, Bcl-2, p53, MDM-2 and caspase pathways. Int J Cancer 82 (1999) 396-404
59. Bhonde M.R., Hanski M.L., Magrini R., Moorthy D., Muller A., Sausville E.A., et al. The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-x(L) protein. Oncogene 24 (2005) 148-156
60. Akinaga S., Nomura K., Gomiand K., and Okabe M. Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. Cancer Chemother Pharmacol 32 (1993) 183-189
61. Bunch R.T., and Eastman A. Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin Cancer Res 2 (1996) 791-797
62. Hsueh C.T., Kelsen D., and Schwartz G.K. UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. Clin Cancer Res 4 (1998) 2201-2206
63. Wang Q., Fan S., Eastman A., Worland P.J., Sausville E.A., and O'Connor P.M. UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 88 (1996) 956-965
64. Seynaeve C.M., Kazanietz M.G., Blumberg P.M., Sausville E.A., and Worland P.J. Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol Pharmacol 45 (1994) 1207-1214
65. Amornphimoltham P., Sriuranpong V., Patel V., Benavides F., Conti C.J., Sauk J., et al. Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin Cancer Res 10 (2004) 4029-4037
66. Kondapaka S.B., Zarnowski M., Yver D.R., Sausville E.A., and Cushman S.W. 7-hydroxystaurosporine (UCN-01) inhibition of Akt Thr308 but not Ser473 phosphorylation: a basis for decreased insulin-stimulated glucose transport. Clin Cancer Res 10 (2004) 7192-7198
67. Komander D., Kular G.S., Bain J., Elliott M., Alessi D.R., and Van Aalten D.M. Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition. Biochem J 375 (2003) 255-262
68. Zhao B., Bower M.J., McDevitt P.J., Zhao H., Davis S.T., Johanson K.O., et al. Structural basis for Chk1 inhibition by UCN-01. J Biol Chem 277 (2002) 46609-46615
69. Fuse E., Kuwabara T., Sparreboom A., Sausville E.A., and Figg W.D. Review of UCN-01 development: a lesson in the importance of clinical pharmacology. J Clin Pharmacol 45 (2005) 394-403
70. Katsuki M., Chuang V.T., Nishi K., Kawahara K., Nakayama H., Yamaotsu N., et al. Use of photoaffinity labeling and site-directed mutagenesis for identification of the key residue responsible for extraordinarily high affinity binding of UCN-01 in human alpha1-acid glycoprotein. J Biol Chem 280 (2005) 1384-1391
71. Fabbro D., Ruetz S., Bodis S., Pruschy M., Csermak K., Man A., et al. PKC412-a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des 15 (2000) 17-28
72. Dees E.C., Baker S.D., O'Reilly S., Rudek M.A., Davidson S.B., Aylesworth C., et al. A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res 11 (2005) 664-671
73. Kortmansky J., Shah M.A., Kaubisch A., Weyerbacher A., Yi S., Tong W., et al. Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors. J Clin Oncol 23 (2005) 1875-1884
74. Sampath D., Cortes J., Estrov Z., Du M., Shi Z., Andreeff M., et al. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 107 (2006) 2517-2524
75. Meyer T., Regenass U., Fabbro D., Alteri E., Rosel J., Muller M., et al. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer 43 (1989) 851-856
76. Fabbro D., Buchdunger E., Wood J., Mestan J., Hofmann F., Ferrari S., et al. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. Pharmacol Ther 82 (1999) 293-301
77. Utz I., Hofer S., Regenass U., Hilbe W., Thaler J., Grunicke H., et al. The protein kinase C inhibitor CGP 41251, a staurosporine derivative with antitumor activity, reverses multidrug resistance. Int J Cancer 57 (1994) 104-110
78. Utz I., Spitaler M., Rybczynska M., Ludescher C., Hilbe W., Regenass U., et al. Reversal of multidrug resistance by the staurosporine derivatives CGP 41251 and CGP 42700. Int J Cancer 77 (1998) 64-69
79. Beltran P.J., Fan D., Fidler I.J., and O'Brian C.A. Chemosensitization of cancer cells by the staurosporine derivative CGP 41251 in association with decreased P-glycoprotein phosphorylation. Biochem Pharmacol 53 (1997) 245-247
80. Begemann M., Kashimawo S.A., Heitjan D.F., Schiff P.B., Bruce J.N., and Weinstein I.B. Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity. Anticancer Res 18 (1998) 2275-2282
81. Rocha S., Soengas M.S., Lowe S.W., Glanzmann C., Fabbro D., Winterhalter K., et al. Protein kinase C inhibitor and irradiation-induced apoptosis: relevance of the cytochrome c-mediated caspase-9 death pathway. Cell Growth Differ 11 (2000) 491-499
82. Zaugg K., Rocha S., Resch H., Hegyi I., Oehler C., Glanzmann C., et al. Differential p53-dependent mechanism of radiosensitization in vitro and in vivo by the protein kinase C-specific inhibitor PKC412. Cancer Res 61 (2001) 732-738
83. Tenzer A., Zingg D., Rocha S., Hemmings B., Fabbro D., Glanzmann C., et al. The phosphatidylinositide 3'-kinase/Akt survival pathway is a target for the anticancer and radiosensitizing agent PKC412, an inhibitor of protein kinase C. Cancer Res 61 (2001) 8203-8210
84. Virchis A., Ganeshaguru K., Hart S., Jones D., Fletcher L., Wright F., et al. A novel treatment approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C. Hematol J 3 (2002) 131-136
85. Ganeshaguru K., Wickremasinghe R.G., Jones D.T., Gordon M., Hart S.M., Virchis A.E., et al. Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica 87 (2002) 167-176
86. Seo M.S., Kwak N., Ozaki H., Yamada H., Okamoto N., Yamada E., et al. Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor. Am J Pathol 154 (1999) 1743-1753
87. Campochiaro P.A. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci 45 (2004) 922-931
88. Cools J., Stover E.H., Boulton C.L., Gotlib J., Legare R.D., Amaral S.M., et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease. Cancer Cell 3 (2003) 459-469
89. Debiec-Rychter M., Cools J., Dumez H., Sciot R., Stul M., Mentens N., et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 128 (2005) 270-279
90. Growney J.D., Clark J.J., Adelsperger J., Stone R., Fabbro D., Griffin J.D., et al. Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood 106 (2005) 721-724
91. Gotlib J., Berube C., Growney J.D., Chen C.C., George T.I., Williams C., et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 106 (2005) 2865-2870
92. Gilliland D.G., and Griffin J.D. The roles of FLT3 in hematopoiesis and leukemia. Blood 100 (2002) 1532-1542
93. Gilliland D.G., and Tallman M.S. Focus on acute leukemias. Cancer Cell 1 (2002) 417-420
94. Kelly L., Clark J., and Gilliland D.G. Comprehensive genotypic analysis of leukemia: clinical and therapeutic implications. Curr Opin Oncol 14 (2002) 10-18
95. Weisberg E., Boulton C., Kelly L.M., Manley P., Fabbro D., Meyer T., et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1 (2002) 433-443
96. Smith B.D., Levis M., Beran M., Giles F., Kantarjian H., Berg K., et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103 (2004) 3669-3676
97. Stone R.M., DeAngelo D.J., Klimek V., Galinsky I., Estey E., Nimer S.D., et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105 (2005) 54-60
98. Stone R.M., Fischer T., Paquette R., Schiller G., Schiffer C.A., Ehninger G., et al. Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed patients with AML. ASH Annual Meeting Abstracts 106 (2005) 404
99. Levis M., Smith B.D., Beran M., Baer M.R., Erba H.P., Cripe L., et al. A Randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 Inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition. ASH Annual Meeting Abstracts 106 (2005) 403
100. Levis M., Brown P., Smith B.D., Stine A., Pham R., Stone R., et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 108 (2006) 3477-3483
101. Cools J., Mentens N., Furet P., Fabbro D., Clark J.J., Griffin J.D., et al. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res 64 (2004) 6385-6389
102. Heidel F., Solem F.K., Breitenbuecher F., Lipka D.B., Kasper S., Thiede M.H., et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 107 (2006) 293-300
103. Chen J., Deangelo D.J., Kutok J.L., Williams I.R., Lee B.H., Wadleigh M., et al. PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci USA 101 (2004) 14479-14484
104. Pearce H.L., and Alice Miller M. The evolution of cancer research and drug discovery at Lilly Research Laboratories. Adv Enzyme Regul 45 (2005) 229-255
105. Toullec D., Pianetti P., Coste H., Bellevergue P., Grand-Perret T., Ajakane M., et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 266 (1991) 15771-15781
106. Faul M.M., Gillig J.R., Jirousek M.R., Ballas L.M., Schotten T., Kahl A., et al. Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCbeta. Bioorg Med Chem Lett 13 (2003) 1857-1859
107. Keyes K.A., Mann L., Sherman M., Galbreath E., Schirtzinger L., Ballard D., et al. LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 53 (2004) 133-140
108. Podar K., Raab M.S., Zhang J., McMillin D., Breitkreutz I., Tai Y.T., et al. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor Enzastaurin (LY317615.HCl). Blood (2006)
109. Rizvi M.A., Ghias K., Davies K.M., Ma C., Weinberg F., Munshi H.G., et al. Enzastaurin (LY317615), a protein kinase Cbeta inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines. Mol Cancer Ther 5 (2006) 1783-1789
110. Teicher B.A., Alvarez E., Menon K., Esterman M.A., Considine E., Shih C., et al. Antiangiogenic effects of a protein kinase Cbeta-selective small molecule. Cancer Chemother Pharmacol 49 (2002) 69-77
111. Teicher B.A., Menon K., Alvarez E., Shih C., and Faul M.M. Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human breast cancer and ovarian cancer xenografts. Invest New Drugs 20 (2002) 241-251
112. Carducci M.A., Musib L., Kies M.S., Pili R., Truong M., Brahmer J.R., et al. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 24 (2006) 4092-4099
113. Green L.J., Marder P., Ray C., Cook C.A., Jaken S., Musib L.C., et al. Development and validation of a drug activity biomarker that shows target inhibition in cancer patients receiving enzastaurin, a novel protein kinase C-beta inhibitor. Clin Cancer Res 12 (2006) 3408-3415
114. Hofmann J. Modulation of protein kinase C in antitumor treatment. Rev Physiol Biochem Pharmacol 142 (2001) 1-96
115. Lee H.W., Smith L., Pettit G.R., Vinitsky A., and Smith J.B. Ubiquitination of protein kinase C-alpha and degradation by the proteasome. J Biol Chem 271 (1996) 20973-20976
116. Clamp A., and Jayson G.C. The clinical development of the bryostatins. Anticancer Drugs 13 (2002) 673-683
117. Mackay H.J., and Twelves C.J. Protein kinase C: a target for anticancer drugs?. Endocr Relat Cancer 10 (2003) 389-396
118. Swannie H.C., and Kaye S.B. Protein kinase C inhibitors. Curr Oncol Rep 4 (2002) 37-46
119. Szallasi Z., Smith C.B., Pettit G.R., and Blumberg P.M. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. J Biol Chem 269 (1994) 2118-2124
120. Hocevar B.A., and Fields A.P. Selective translocation of beta II-protein kinase C to the nucleus of human promyelocytic (HL60) leukemia cells. J Biol Chem 266 (1991) 28-33
121. Propper D.J., Macaulay V., O'Byrne K.J., Braybrooke J.P., Wilner S.M., Ganesan T.S., et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br J Cancer 78 (1998) 1337-1341
122. Zonder J.A., Shields A.F., Zalupski M., Chaplen R., Heilbrun L.K., Arlauskas P., et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin Cancer Res 7 (2001) 38-42
123. Varterasian M.L., Mohammad R.M., Eilender D.S., Hulburd K., Rodriguez D.H., Pemberton P.A., et al. Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia. J Clin Oncol 16 (1998) 56-62
124. Dean N.M., McKay R., Condon T.P., and Bennett C.F. 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. J Biol Chem 269 (1994) 16416-16424
125. Hanauske A.R., Sundell K., and Lahn M. The role of protein kinase C-alpha (PKC-alpha) in cancer and its modulation by the novel PKC-alpha-specific inhibitor aprinocarsen. Curr Pharm Des 10 (2004) 1923-1936
126. Jansen B., and Zangemeister-Wittke U. Antisense therapy for cancer-the time of truth. Lancet Oncol 3 (2002) 672-683
127. Dias N., and Stein C.A. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 1 (2002) 347-355
128. Denham D.W., Franz M.G., Denham W., Zervos E.E., Gower Jr. W.R., Rosemurgy A.S., et al. Directed antisense therapy confirms the role of protein kinase C-alpha in the tumorigenicity of pancreatic cancer. Surgery 124 (1998) 218-223 discussion 223-4
129. Shen L., Dean N.M., and Glazer R.I. Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase C alpha antisense oligonucleotide. Mol Pharmacol 55 (1999) 396-402
130. Dennis J.U., Dean N.M., Bennett C.F., Griffith J.W., Lang C.M., and Welch D.R. Human melanoma metastasis is inhibited following ex vivo treatment with an antisense oligonucleotide to protein kinase C-alpha. Cancer Lett 128 (1998) 65-70
131. Yazaki T., Ahmad S., Chahlavi A., Zylber-Katz E., Dean N.M., Rabkin S.D., et al. Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide. Mol Pharmacol 50 (1996) 236-242
132. Galderisi U., Cascino A., and Giordano A. Antisense oligonucleotides as therapeutic agents. J Cell Physiol 181 (1999) 251-257
133. Li K., and Zhang J. ISIS-3521. Isis pharmaceuticals. Curr Opin Investig Drugs 2 (2001) 1454-1461
134. Villalona-Calero M.A., Ritch P., Figueroa J.A., Otterson G.A., Belt R., Dow E., et al. A phase I/II study of LY900003, an antisense inhibitor of protein kinase C-alpha, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer. Clin Cancer Res 10 (2004) 6086-6093
135. Marshall J.L., Eisenberg S.G., Johnson M.D., Hanfelt J., Dorr F.A., El-Ashry D., et al. A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer. Clin Colorectal Cancer 4 (2004) 268-274
136. Cripps M.C., Figueredo A.T., Oza A.M., Taylor M.J., Fields A.L., Holmlund J.T., et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin Cancer Res 8 (2002) 2188-2192
137. Advani R., Peethambaram P., Lum B.L., Fisher G.A., Hartmann L., Long H.J., et al. A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C alpha, administered as a 21-day infusion to patients with advanced ovarian carcinoma. Cancer 100 (2004) 321-326
138. Roychowdhury D., and Lahn M. Antisense therapy directed to protein kinase C-alpha (Affinitak, LY900003/ISIS 3521): potential role in breast cancer. Semin Oncol 30 (2003) 30-33
139. Tolcher A.W., Reyno L., Venner P.M., Ernst S.D., Moore M., Geary R.S., et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res 8 (2002) 2530-2535
140. Rao S., Watkins D., Cunningham D., Dunlop D., Johnson P., Selby P., et al. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma. Ann Oncol 15 (2004) 1413-1418
141. Yuen A.R., Halsey J., Fisher G.A., Holmlund J.T., Geary R.S., Kwoh T.J., et al. Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. Clin Cancer Res 5 (1999) 3357-3363
142. Ritch P., Rudin C.M., Bitran J.D., Edelman M.J., Makalinao A., Irwin D., et al. Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer 52 (2006) 173-180
143. Schwartz G.K., Ward D., Saltz L., Casper E.S., Spiess T., Mullen E., et al. A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin Cancer Res 3 (1997) 537-543
144. Ferry D.R., Smith A., Malkhandi J., Fyfe D.W., deTakats P.G., Anderson D., et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2 (1996) 659-668
145. Mulholland P.J., Ferry D.R., Anderson D., Hussain S.A., Young A.M., Cook J.E., et al. Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin. Ann Oncol 12 (2001) 245-248
146. da Rocha A.B., Mans D.R., Bernard E.A., Ruschel C., Logullo A.F., Wetmore L.A., et al. Tamoxifen inhibits particulate-associated protein kinase C activity, and sensitises cultured human glioblastoma cells not to etoposide but to gamma-radiation and BCNU. Eur J Cancer 35 (1999) 833-839
147. Couldwell W.T., Hinton D.R., Surnock A.A., DeGiorgio C.M., Weiner L.P., Apuzzo M.L., et al. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 2 (1996) 619-622
148. Bergan R.C., Reed E., Myers C.E., Headlee D., Brawley O., Cho H.K., et al. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin Cancer Res 5 (1999) 2366-2373
149. Smorenburg C.H., Seynaeve C., Bontenbal M., Planting A.S., Sindermann H., and Verweij J. Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Anticancer Drugs 11 (2000) 825-828
150. Choi C.H. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5 (2005) 30
151. Gottesman M.M., Fojo T., and Bates S.E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2 (2002) 48-58
152. Idriss H.T., Hannun Y.A., Boulpaep E., and Basavappa S. Regulation of volume-activated chloride channels by P-glycoprotein: phosphorylation has the final say!. J Physiol 524.3 (2000) 629-636