Targeting the protein kinase C family: Are we there yet?

Nature Reviews Cancer

Volumn 7, Issue 7, 2007, Pages 554-562

  Mackay, Helen J ^a   Twelves, Christopher J ^b  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY OF BRADFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

12 (2 CYANOETHYL) 6,7,12,13 TETRAHYDRO 13 METHYL 5 OXOINDOLO[2,3 A]PYRROLO[3,4 C]CARBAZOLE; 7 HYDROXYSTAUROSPORINE; ANTINEOPLASTIC AGENT; APRINOCARSEN; BRYOSTATIN 1; CAMPTOTHECIN; CAPECITABINE; CARBOPLATIN; CISPLATIN; CYTARABINE; DOXORUBICIN; ENZASTAURIN; FLUOROURACIL; GEMCITABINE; ISIS 3521; ISIS 9606; MIDOSTAURIN; MITOMYCIN C; PACLITAXEL; PHORBOL 13 ACETATE 12 MYRISTATE; PREMETEXED; PROTEIN KINASE C; PROTEIN KINASE C INHIBITOR; RUBOXISTAURIN; SAFINGOL; STAUROSPORINE; TAMOXIFEN; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINBLASTINE; VINCRISTINE;

ANGIOGENESIS; APOPTOSIS; CANCER; CANCER CHEMOTHERAPY; CARCINOGENESIS; CELL DIFFERENTIATION; CELL MEMBRANE; CELL MOTILITY; CELL PROLIFERATION; CHILL; CLINICAL TRIAL; COMPARATIVE GENOMIC HYBRIDIZATION; CONTINUOUS INFUSION; CYTOTOXICITY; DIARRHEA; DRUG DOSE ESCALATION; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; FATIGUE; FEVER; GASTROINTESTINAL ABSORPTION; HUMAN; IMMUNOCHEMISTRY; IMMUNOHISTOCHEMISTRY; LUNG NON SMALL CELL CANCER; NAUSEA; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; THROMBOCYTOPENIA; VOMITING;

APOPTOSIS; CELL DIFFERENTIATION; CELL DIVISION; ENZYME INHIBITORS; HUMANS; ISOENZYMES; KINETICS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; NEOVASCULARIZATION, PHYSIOLOGIC; PROTEIN KINASE C; SIGNAL TRANSDUCTION;

EID: 34250902930     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc2168     Document Type: Review

References (132)

1. Fields, A. P. & Gustafson, W. C. in Methods in Molecular Biology (ed. Newton, A. C.) 519-537 (Humana Press Inc., Totowa, New Jersey, 2003).
2. Blobe, G. C., Obeid, L. M. & Hannun, Y. A. Regulation of protein kinase C and role in cancer biology. Cancer Met. Rev. 13, 724-730 (1994).
3. Castagna, M. et al. Direct activation of calcium-activated, phopholipid-dependent protein kinase by tumour-promoting phorbol esters. J. Biol. Chem. 257, 7847-7851 (1982).
4. Mackay, H. & Twelves, C. J. Protein kinase C: a target for anticancer drugs? Endocrine Relat. Cancer 10, 386-396 (2003).
5. Takai, Y. et al. Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids. J. Biol. Chem. 3692-3695 (1979).
6. Newton, A. C. Protein kinase C; structure, function, and regulation. J. Biol. Chem. 270, 28495-28498 (1995).
7. Nishizuka, Y. Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science 258, 607-614 (1992).
8. Schenk, P. W. & Snaar-Jagalska, B. E. Signal perception and transduction: the role of protein kinases. Biochem. Biophys. Acta 1449, 1-24 (1999).
9. Disatnik, M. H., Buraggi, G. & Mochly-Rosen, D. Localisation of protein kinase C isozymes in cardiac myocytes. Exp. Cell Res. 210, 287-297 (1994).
10. Csuki, M. and Mochley-Rosen, D. Pharmacologic modulation of protein kinase C isozymes: the role of RACKs and subcellular localisation. Pharmacol. Res. 39, 253-259 (1999).
11. Way, K. J., Chou, E. & King, G. L. Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends Parmacol. Sci. 21, 181-187 (2000).
12. Ohno, S. in Protein kinase C (eds Parker, P. J. & Deckker, L. V.) 75-95 (RG Landes, USA, 1997).
13. Cai, H. et al. Role of diacylglycerol-regulated protein kinase C isotypes in growth factor activation of the Raf-1 protein kinase. Mol. Cell. Biol. 17, 732-741 (1997).
14. Marshall, C. J. Cell signalling; Raf gets it together. Nature 383, 127-128 (1996).
15. Ueda, Y. et al. Protein kinase C δ activates the MER-KERK pathway in a manner independent of Ras and dependent on Raf. J. Biol. Chem. 271, 23512-23519 (1996).
16. Balendran, A. et al. Further evidence that 3-phosphoin ositidedependent protein kinase-1 (PDK1) is required for thestability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett. 484, 217-223 (2000).
17. O'Brian, C. A., Liskamp, R. M., Solomon, D. H. & Weinstein, I. B. Inhibition of protein kinase C by tamoxifen. Cancer Res. 45, 2462-2465 (1985).
18. Takenaga, K. & Takahashi, K. Effects of 12-O-tetradecanoylphorbol-13- acetate on adhesiveness and lung-colonising ability of Lewis lung carcinoma cells. Cancer Res. 46, 375-380 (1996).
19. Schwartz, G. K., Juang, K., Kelsen, D. & Albino, A. P. Protein kinase C: a novel target for inhibiting gastric cancer cell invasion. J. Natl Cancer Inst. 85, 402-407 (1993).
20. Murray, N. R. et al. Protein kinase C isotypes in human erythroleukaemia (K562) cell proliferation and differentiation. Evidence that βII protein kinase C is required for proliferation. J. Biol Chem. 268, 15847-15853 (1993).
21. Murray, N. R. et al. Overexpression of protein kinase C βII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis. J. Cell Biol. 145, 699-711 (1999).
22. Black, J. D. Protein kinase C isozymes in colon carcinogenesis: guilt by omission. Gastroenterology 120, 1868-1872 (2001).
23. Gokmen-Polar, Y. et al. Elevated protein kinase C βII is an early promotive event in colon carcinogenesis. Cancer Res. 61, 1375-1381 (2001).
24. Suga, K. et al. Down-regulation of protein kinase C α detected in human colorectal cancer. Biochem. Mol. Biol. Int. 44, 523-528 (1998).
25. O' Brian, C. A., Vogel, V. G., Singletary, S. E. & Ward, N. E. Elevated protein kinase C expression in human breast tumour biopsies relative to normal breast tissue. Cancer Res. 49, 3215-3217 (1989).
26. +-dependent protein kinase of human mammary carcinoma cells: inverse relationship to estrogen receptors. Int. J. Cancer 40, 344-348 (1987).
27. Manni, A. et al. Induction of a less aggressive breast cancer phenotype by protein kinase C-α and β-overexpression. Cell Growth Differ. 7, 1187-1198 (1996).
28. Xia, P. et al. Characterisation of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J. Clin. Invest. 98, 2018-2026 (1996).
29. Cohen, E. E. et al. Protein kinase C ζ mediates EGF-induced growth of head and neck tumor cells regulating MAP kinase. Proc. Amer. Assoc. Cancer Res. 47, abs. 70 (2006).
30. Herbert, J. M. Protein kinase C: a key factor in the regulation of tumor cell adhesion to the endothelium. Biochem. Pharmacol. 45, 527-537 (1993).
31. Morse-Gaudio, M., Connolly, J. M. & Rose, D. P. Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype. Int. J. Oncol. 12, 1349-1354 (1998).
32. Ways, D. K. et al. MCF7 breast cancer cells transfected with protein kinase C-α exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. J. Clin. Invest. 95, 1906-1915 (1995).
33. Lee, J. Y., Hannun, Y. A. & Obeid, L. M. Ceramide inactivates cellular protein kinase C alpha. J. Biol. Chem. 271, 13169-13174 (1996).
34. Goss, V. L., Hocevar, B. A. & Thompson, L. J. Identification of nuclear β II protein kinase C as a mitotic lamin kinase. J. Biol. Chem. 269, 19074-19080 (1994).
35. Ruvolo, P. P., Deng, X. & Carr, B. K. A functional role for mitochondrial protein kinase C α in Bcl2 phosphorylation and suppression of apoptosis. J. Biol. Chem. 273, 25436-25422 (1998).
36. Wert, M. M. & Palfrey, H. C. Divergence in the apoptotic signaling pathways used by nerve growth factor and basic fibroblast growth factor (bFGF) in PC12 cells: Rescue by bFGF involves protein kinase C δ. Biochem. J. 352, 175-182 (2000).
37. Cross, T, Griffiths, G. & Deacon, E. PKC is an apoptotic lamin kinase. Oncogene 19, 2331-2337 (2000).
38. Mandil, A. S., Ashkenazi, E. & Blass, M. Protein kinase C α and protein kinase C δ play opposite roles in the proliferation and apoptosis of glioma cells. Cancer Res. 61, 4612-4619 (2001).
39. Clark, A. S, West, K. A. & Blumberg, P. M. Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCδ promotes cellular survival and chemotherapeutic resistance. Cancer Res. 63, 780-786 (2003).
40. Partovian, C. & Simons, M. Regulation of protein kinase B/Akt activity and Ser473 phosphorylation by protein kinase Ca in endothelial cells. Cell. Signal. 16, 951-957 (2004).
41. Kawakami, Y. et al. Protein kinase C hII regulates Akt phosphorylation on Ser-473 in a cell type- and stimulus-specific fashion. J. Biol. Chem. 279, 47720-47725 (2004).
42. Aeder, S. E. et al. PKC- mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene 23, 9062-9069 (2004).
43. Fang, X. et al. Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid througha protein kinase C-dependent intracellular pathway. Mol. Cell. Biol. 22, 2099-2110 (2002).
44. Goode, N. et al. Differential regulation of glycogen synthase kinase-3 η by protein kinase C isotypes. J. Biol. Chem. 267, 16878-16882 (1992).
45. Cross, D. A. et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789 (1995).
46. Teicher, B. A. et al. Antiangiogenic effects of a protein kinase C β-selective small molecule. Cancer Chemother. Pharmacol. 49, 69-77 (2002).
47. Fine, R. L., Patel, J. & Chabner, B. A. Phorbol esters induce multidrug resistance in human breast cancer cells. Proc. Natl Acad. Sci. 85, 582-586 (1988).
48. O'Brian, C. A., Ward, N. E., Stewart, J. R. & Chu, F. Prospects for targeting protein kinase C isozymes in the therapy of drug-resistant cancer-an evolving story. Cancer Met. Rev. 20, 95-100 (2001).
49. Germann, U. A. et al. Characterisation of phosphorylation - defective mutants of human P-glycoprotein expressed in mammalian cells. J. Biol. Chem. 271, 1708-1716 (1996).
50. Goodfellow, H. R. et al. Protein kinase C mediated phosphorylation does not regulate drug transport by the human multidrug resistance P-glycoprotein. J. Biol. Chem. 271, 13668-13674 (1996).
51. Beck, J. F., Brugger, D. & Brischwein, K. Anticancer drug-mediated induction of multidrug resistance-associated genes and protein kinase C isozymes in the T-lymphoblastoid cell line CCRF-CEM and in blasts from patients with acute lymphoblastic leukemias. Jpn J. Cancer Res. 92, 896-903 (2001).
52. Ainsworth, P. D. et al. Protein kinase C α expression in normal breast, ductal carcinoma in situ and invasive carcinoma. Euro. J. Cancer 40, 2269-2273 (2004).
53. Varga, A. et al. Tumor grade-dependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas. Eur. Urol. 24, 462-465 (2004).
54. Weichart, W. et al. Protein kinase C isoform expression in ovarian cancer correlates with indicators of poor prognosis. Int. J. Oncol. 23, 633-639 (2003).
55. Fournier, D. B. et al. Protein kinase C expression is inversely related to ER status in endometrial cancer: possible role in AP-1 mediated proliferation of ER negative endometrial cancer. Gynecol. Oncol. 81, 366-372 (2001).
56. Cornford, P. et al. Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer. Am. J. Pathol. 54, 137-144 (1999).
57. Ahang, L. et al. Integrative genomic analysis of protein kinase C (PKC) family identifies PKC ι as a biomarker and potential oncogene in ovarian cancer. Cancer Res. 66, 4627-4635 (2006).
58. Lahn, M. et al. Immunohistochemical detection of protein kinase C-β (PKC-β) in tumour specimens of patients with non-small cell lung cancer Histopathology 49, 426-431 (2006).
59. Lahn, M. et al. Expression level of protein kinase C α in non small cell lung cancer. Clin. Lung Cancer 6, 184-189 (2004).
60. Andrejauskas, B. E. & Regenass, U. Differential inhibition of the epidermal growth factor-, platelet-derived growth factor, and protein kinase C-mediated signal transduction pathways by staurosporine derivative CGP41251. Cancer Res. 52, 5353-5358 (1992).
61. Utz, I. et al. The protein kinase inhibitor CGP41251, a staurosporine derivative with antitumour activity, reverses multidrug resistance. Int. J. Cancer 57, 104-110 (1994).
62. Budworth, J. et al. Comparison of staurosporine and four analogues: their effects on growth, rhodamine 123 retention and binding to p-glycoprotein in multidrug-resistant MCF7/Adr cells. Brit. J. Cancer 73, 1063-1068 (1996).
63. Propper, D. J. et al. Phase I and pharmacokinetic study of PKC412 an inhibitor of protein kinase C. J. Clin. Oncol. 19, 1485-1492 (2001).
64. Shapira, L. et al. Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNFα and IL1β production by human monocytes. J. Immunol. 153, 1818-1824 (1994).
65. Norris, J. G. et al. Signal transduction pathways mediating astrocyte IL-6 induction by IL-1β and tumor necrosis factor-α. J. Immunol. 152, 841-850 (1994).
66. ++ signals restore mitogenic activity without abrogating enhanced cPKC degradation. Cell. Immunol. 158, 195-207 (1994).
67. Laxminarayana, D. & Kammer, G. M. Activation of type I protein kinase A during receptor mediated human T lymphocyte activation. J. Immunol. 156, 497-506 (1996).
68. Vang, T. et al. Activation of the COOH-terminal src kinase (Csk) by cAMP-dependent protein kinase inhibits signalling through the T cell receptor. J. Exp. Med. 193, 497-507 (2001).
69. Thavasu P. et al. The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-related kinase 2 expression in cancer patients. Cancer Res. 59, 3980-3984 (1999).
70. Selzer, E. et al. Protein kinase C isoforms in normal and transformed cells of the melanocytic lineage. Melanoma Res. 12, 201-209 (2002).
71. Yoshikawa, N. et al. Effect of PKC412, a selective inhibitor of protein kinase C, on lung metastasis in mice injected with B16 melanoma cells. Life Sci. 72, 1377-1387 (2003).
72. Millward, M. J. et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br. J. Cancer 95, 829-834 (2006).
73. Reichardt, P. et al. A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. Proc. Amer. Soc. Clin. Oncol. 23, 3016 (2005).
74. Ming-Sing, S., Reitz, B. A. & Borie, D. C. Effects of the kinase inhibitor CGP41251(PKC412) on lymphocyte activation and TNF-α production. Int. Immunopharmacol. 5, 1141-1149 (2005).
75. Keyes, K. A. et al. LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother. Pharmacol. 53, 133-140 (2004).
76. Meinhold-Heerlein, I. et al. Effects of PKC β inhibitor enzastaurin on parental and chemoresistant ovarian cancer cell lines. Proc. Amer. Soc. Clin. Oncol. 24, 20037 (2006).
77. Graff, J. R., McNulty, A. M. & Hanna, K. R. The protein kinase C β-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, 7462-7469 (2005).
78. Carducci, M. A. et al. Phase I dose escalation and pharmacokinetic study of Enzastaurin, an oral protein kinase C β inhibitor, in patients with advanced cancer. J. Clin. Oncol. 24, 4092-4099 (2006).
79. Adjei, A. What is the right dose? The elusive optimal biologic dose in phase I clinical trials. J. Clin. Oncol. 24, 4054-4055 (2006).
80. Green, L. J. et al. Development and validation of a drug activity biomarker that shows target inhibition in cancer patients receiving enzastaurin, a novel protein kinase C-β inhibitor. Clin. Cancer. Res. 12, 3408-3415 (2006).
81. Fine, H. A. et al. Results from phase II trial of enzastaurin (LY317615) in patients with recurrent high grade gliomas. Proc. Amer. Soc. Clin. Oncol. 23, 1504 (2005).
82. Rademaker-Lakhai, J. M. et al. Phase I and pharmacologic study of enzastaurin HCL, gemcitabine and cisplatin. Proc. Amer. Soc. Clin. Oncol. 22, 3129 (2004).
83. Leong, S. et al. A phase I dose escalation and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced cancer. Proc. Amer. Soc. Clin. Oncol. 24, 2048 (2006).
84. Schaufelberger, D. E. et al. The large scale isolation of bryostatin 1 from Bugula nerutina following current good manufacturing practices. J. Nat. Prod. 54, 1265-1270 (1991).
85. Smith, J. B., Smith, L. & Pettit, G. R. Bryostatins: potent, new mitogens that mimic phorbol ester tumour promoters. Biochem. Biophys. Res. Commun. 132, 939-945 (1985).
86. Szallasi, Z., Smith, C. B., Pettit, G. R. & Blumberg, P. M. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myrstate 13-acetate in NIH 3t3 fibroblasts. J. Biol. Chem. 269, 2118-2124 (1994).
87. Hocevar, B. A. & Fields, A. P. Selective translocation of βII protein kinase C to the nucleus of human promyelocytic (HL-60) leukemia cells. J. Cell. Biol. 266, 28-33 (1991).
88. Stanwell, C. et al. The role of protein kinase C isoenzymes inhibition caused by bryostatin-1 in human A549 lung and MCF-7 breast carcinoma cells. Int. J. Cancer 56, 584-592 (1994).
89. Hennings, H. et al. Bryostatin 1 activator of protein kinase C inhibits, tumor promotion by phorbol esters in sencar mouse skin. Carcinogenesis 9, 1343-1346 (1987).
90. Lee, H-W. et al. Ubiquitination of protein kinase C α and degradation by the proteosome. J. Biol. Chem. 271, 20973-20976 (1996).
91. Mohr, H., Pettit, G. R. & Plessing-Menze, A. Co-induction of lymphokine synthesis by the antineoplastic bryostatins. Immunobiology 175, 420-430 (1987).
92. Trenn, G. et al. Immunomodulating properties of a novel series of protein kinase C activators. The biostatins. J. Immunol. 140, 433-439 (1988).
93. Jarvis, W. D. et al. Effects of bryostatin 1 and other pharmacological activators of protein kinase C on 1-β-D- arabinofuranosylcytosine-induced apoptosis in HL-60 human promyelocytic leukemia cells. Biochem. Pharmacol. 47, 839-852 (1994).
94. Mohammed, R. M. et al. Bryostatin-1 induces apoptosis and augments inhibitory effects of vincristine in human diffuse large cell lymphoma. Leuk. Res. 19, 667-673(1995).
95. Basu, A. & Lazo, J. S. Sensitization of human cervical carcinoma cells to cis-diamminedichloroplatinum (II) by bryostatin-1. Cancer Res. 52, 3119-3124 (1992).
96. . El-Rayes, B. F. et al. Phase I study of bryostatin I and gemcitabine. Clin. Cancer Res. 12, 7059-7062 (2006).
97. Koutcher J. A. et al. The in vivo effect of bryostatin-1 on paclitaxel-induced tumor growth, mitotic entry, and blood flow. Clin. Cancer Res. 6, 1498-1507 (2000).
98. Philip, P. A. et al. Phase I study of bryostatin 1: assessment of interleukin 6 and tumour necrosis factor alpha induction in vivo. J. Natl Cancer Inst. 85, 1812-1818 (1993).
99. Prendiville, J. et al. A phase I study of intravenous bryostatin 1 in patients with advanced cancer. Br. J. Cancer 68, 418-424 (1993).
100. Jayson, G. C. et al. A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour infusion. Br. J. Cancer. 72, 461-468 (1995).
101. Propper, D. J. et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br. J. Cancer 78, 1337-1341 (1998).
102. Zonder, J. A. et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res. 7, 38-42 (2001).
103. Kaubisch, A. et al. Phase II study of sequential paclitaxel (P) and bryostatin-1 (bryo) for patients with advanced pancreatic cancer. Proc. Amer. Soc. Clin. Oncol. 22, 4223 (2004).
104. Hudes, G. R. et al. Phase II study of weekly paclitaxel (PAC) and brostatin-1 (bryo) in hormone refractory prostate cancer (HRPC). Proc. Amer. Soc. Clin. Oncol. 23, 4714 (2005).
105. Peterson, A. C. et al. A randomized phase II trial of interleukin-2 in combination with four different doses of bryostatin in patients with renal cell carcinoma. Proc. Amer. Soc. Clin. Oncol. 22, 4608 (2004).
106. Haas, N. B. et al. Phase I study of intravenous CCI-779 in combination with bryostatin-1 in solid tumors. Proc. Amer. Soc. Clin. Oncol. 24, 3067 (2006).
107. Dean, N. M., McKay, R., Condon, T. P. & Bennett, C. F. Inhibition of protein kinase C-α expression in human A549 cells by antisense oligonucleotides inhibits induction of intracellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J. Biol. Chem. 269, 16416-16424 (1994).
108. Dean, N. M. et al. Inhibition of growth of human tumour cell lines in nude mice by an antisense oligonucleotide inhibitor of protein kinase C α expression. Cancer Res. 56, 3499-3507 (1996).
109. Yazaki T et al. Treatment of gioblastoma U-87 by systemic administration by an antisense protein kinase Cα phosphothioate oligodeoxynucleotide. Mol. Pharmacol. 50, 236-242 (1996).
110. Neumunaitis, J. et al. Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-α, in patients with advanced cancer. J. Clin. Oncol. 17, 3586-3595 (1999).
111. Gradishar, W. J. et al. A phase II trial with antisense oligonucleotide ISIS 3521/Cgp 64128a in patients (Pts) with metastatic breast cancer (MBC): ECOG Trial 3197. Proc. Amer. Soc. Clin. Oncol. 20, abs. 171 (2001).
112. Grossman S. D. et al. Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-α delivered as a 21 day continuous intraveneous infusion in patients with recurrent high-grade astrocytomas. Neuro-oncol. 7, 32-40 (2005).
113. Yuen, A. R. et al. Phase I/II trial of ISIS 3521, an antisense inhibitor of PKC-α, with carboplatin and paclitaxel in non-small cell lung cancer. Proc. Amer. Soc. Clin. Oncol. 20, abs 1234 (2001).
114. Ritch, P. et al. Phase II study of PKCα antisense oligonucleotide aprinocarsen in combination with gemcitabine and cisplatin in patients with advanced non small cell lung cancer. Lung Cancer 52, 173-180 (2006).
115. Paz-Ares, L et al. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-α antisense oligonucleotide, in patients with advanced stage non-small-cell lung cancer. J. Clin. Oncol. 24, 1428-1434 (2006).
116. Lynch T. J. et al. Randomized phase III trial of chemotherapy and anti sense, oligonucleotide LY9000003 (ISIS 3521) in patients with advanced NSCLC: initial report. Proc. Am. Soc. Clin. Oncol. 22, 623 abs. 2504 (2003).
117. Jane, E. P., Premkumar, D. R. & Pollack, I. F. Coadministration of sorafenib with rotterlin potently inhibits cell proliferation and migration in human malignant glioma cells. J. Pharmacol. Exp. Ther. 319, 1070-1080 (2006).
118. Schaar, D. et al. A phase I clinical trial of 12-O- tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies. Cancer Chemother. Pharmacol. 57, 789-795 (2006).
119. Mizuno, K., Saido, T. C., Ohno, S., Tamaoki, T. & Suzuki, K. Staurosporine-related compounds, K252a and UCN01, inhibit both cPKC and n PKC. FEBS lett. 330, 114-116 (1993).
120. Jones, C. B. et al. Enhancement of camptothecin-induced cytotoxicity with UCN01 in breast cancer cells: abrogation of S/G2 arrest. Cancer Chemother. Pharmacol. 45, 252-258 (2000).
121. Bunch, R. T. & Eastman, A. Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN01) a new G2-checkpoint inhibitor 1996. Clin. Cancer Res. 2 791-797.
122. Sugiyama, K. et al. UCN01 selectively enhances mitomycin C cytotoxicity in p53 defective cells which is mediated through S and/or G2 checkpoint abrogation. Int. J. Cancer 85, 703-709 (2000).
123. Fuse, E. et al. Altered pharmacokinetics of a novel anticancer drug, UCN01, caused by specific high affinity binding to α1-acid glycoprotein in humans. Cancer Res. 58, 1054-1060 (1999).
124. Sausville, E. A. et al. Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J. Clin. Oncol. 19, 2319-2333 (2001).
125. Dees, E. 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, 664-667 (2005).
126. Martiny-Baron, G. et al. Selective inhibition of protein kinase C isozymes by the indolocarbazole G06976. J. Biol. Chem. 268, 9194-9197 (1993).
127. O'Brian, C. A., Liskamp, R. M., Solomon, D. H. & Weinstein, I. B. Inhibition of protein kinase C by tamoxifen. Cancer Res. 45, 2462-2465 (1985).
128. Wilkinson, S. E., Parker, P. J. & Nixon, J. S. Isoenzyme specificity of bisindolylmaleimides selective inhibitors of protein kinase C. Biochem. J. 294, 335-337 (1993).
129. Hanauske A et al. Pharmacokinetic interaction and safety of enzastaurin and premetrexed in patients with advanced or metastatic cancer. Proc. Amer. Soc. Clin. Onc. 24, 2047 (2006).
130. Carvajal, R. D. et al. A phase I clinical trial of safingol followed by cisplatin: promising activity in refractory adrenocortical cancer with novel pharmacology. Proc. Amer. Soc. Clin. Oncol. 24, 13044 (2006).
131. Hirte, H. A phase II study of UCN 01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a Princess Margaret Phase II Consortium trial. Proc. Amer. Soc. Clin. Oncol. 23, 3127 (2005).
132. Kortmansky, J. et al. Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystauroporine in combination with fluorouracil in patients with advanced solid tumors. J. Clin. Oncol. 25, 1875-1884 (2005).