The pros and cons of targeting protein kinase c (PKC) in the management of cancer patients

Current Pharmaceutical Biotechnology

Volumn 12, Issue 11, 2011, Pages 1961-1973

  Coluccio Leskow, F ^a   Krasnapolski, M A ^a   Urtreger, A J ^a  

^a UNIVERSIDAD DE BUENOS AIRES   (Argentina)

Author keywords

Cancer; Clinical trials; PKC

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; PROTEIN KINASE C; PROTEIN KINASE INHIBITOR;

BREAST CANCER; CANCER GROWTH; CANCER PATIENT; CANCER RESEARCH; CARCINOGENESIS; COLON CANCER; DEREGULATION; DRUG TARGETING; HUMAN; LUNG CANCER; MALIGNANT TRANSFORMATION; NONHUMAN; PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION; SKIN CANCER;

EID: 83455259701     PISSN: 13892010     EISSN: 18734316     Source Type: Journal    
DOI: 10.2174/138920111798376950     Document Type: Review

References (132)

1. Kikkawa, U.; Takai, Y.; Tanaka, Y.; Miyake, R.; Nishizuka, Y. Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters. J. Biol. Chem., 1983, 258(19), 11442-11445.
2. Sharkey, N. A.; Leach, K. L.; Blumberg, P. M. Competitive inhibition by diacylglycerol of specific phorbol ester binding. Proc. Natl. Acad. Sci. USA, 1984, 81(2), 607-610.
3. Dekker, L.V.; Parker, P. J. Protein kinase C--a question of specificity. Trends Biochem. Sci., 1994, 19(2), 73-77.
4. Kiley, S. C.; Clark, K. J.; Duddy, S. K.; Welch, D. R.; Jaken, S. Increased protein kinase C delta in mammary tumor cells: relationship to transformtion and metastatic progression. Oncogene, 1999, 18(48), 6748-6757.
5. Nishizuka, Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J., 1995, 9(7), 484-496.
6. Gomez, D. E.; Skilton, G.; Alonso, D. F.; Kazanietz, M. G. The role of protein kinase C and novel phorbol ester receptors in tumor cell invasion and metastasis (Review). Oncol. Rep., 1999, 6(6), 1363-1370.
7. Gordge, P. C.; Hulme, M. J.; Clegg, R. A.; Miller, W. R. Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue. Eur. J. Cancer, 1996, 32A(12), 2120-2126.
8. Gokmen-Polar, Y.; Murray, N.R.; Velasco, M.A.; Gatalica, Z.; Fields, A. P. Elevated protein kinase C betaII is an early promotive event in colon carcinogenesis. Cancer Res., 2001, 61(4), 1375-1381.
9. Kennedy, M. J.; Prestigiacomo, L. J.; Tyler, G.; May, W. S.; Davidson, N. E. Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res., 1992, 52(5), 1278-1283.
10. Sledge, G. W. Jr.; Gokmen-Polar, Y. Protein kinase C-beta as a therapeutic target in breast cancer. Semin. Oncol., 2006, 33(3 Suppl 9), S15-18.
11. Tenzer, A.; Zingg, D.; Rocha, S.; Hemmings, B.; Fabbro, D.; Glanzmann, C.; Schubiger, P. A.; Bodis, S.; Pruschy, M. 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., 2001, 61(22), 8203-8210.
12. Kruger, E. A.; Blagosklonny, M. V.; Dixon, S. C.; Figg, W. D. UCN-01, a protein kinase C inhibitor, inhibits endothelial cell proliferation and angiogenic hypoxic response. Invasion Metastasis, 1998, 18(4), 209-218.
13. Ikegami, Y.; Yano, S.; Nakao, K. Antitumor effect of CGP41251, a new selective protein kinase C inhibitor, on human non-small cell lung cancer cells. Jpn. J. Pharmacol., 1996, 70(1), 65-72.
14. Dean, N.; McKay, R.; Miraglia, L.; Howard, R.; Cooper, S.; Giddings, J.; Nicklin, P.; Meister, L.; Ziel, R.; Geiger, T.; Muller, M.; Fabbro, D. Inhibition of growth of human tumor cell lines in nude mice by an antisense of oligonucleotide inhibitor of protein kinase C-alpha expression. Cancer Res., 1996, 56(15), 3499-3507.
15. Dennis, J. U.; Dean, N. M.; Bennett, C. F.; Griffith, J. W.; Lang, C.M.; Welch, D. R. Human melanoma metastasis is inhibited following ex vivo treatment with an antisense oligonucleotide to protein kinase C-alpha. Cancer Lett., 1998, 128(1), 65-70.
16. Mellor, H.; Parker, P. J. The extended protein kinase C superfamily. Biochem. J., 1998, 332 (Pt 2), 281-292.
17. Newton, A. C. Regulation of protein kinase C. Curr. Opin. Cell Biol., 1997, 9(2), 161-167.
18. Newton, A. C. Protein kinase C: structure, function, and regulation. J. Biol. Chem., 1995, 270(48), 28495-28498.
19. Colon-Gonzalez, F.; Kazanietz, M. G. C1 domains exposed: from diacylglycerol binding to protein-protein interactions. Biochim. Biophys. Acta, 2006, 1761(8), 827-837.
20. Parekh, D. B.; Ziegler, W.; Parker, P. J. Multiple pathways control protein kinase C phosphorylation. EMBO J., 2000, 19(4), 496-503.
21. Leontieva, O.V.; Black, J. D. Identification of two distinct pathways of protein kinase Calpha down-regulation in intestinal epithelial cells. J. Biol. Chem., 2004, 279(7), 5788-5801.
22. Kolch, W.; Heidecker, G.; Kochs, G.; Hummel, R.; Vahidi, H.; Mischak, H.; Finkenzeller, G.; Marme, D.; Rapp, U. R. Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature, 1993, 364(6434), 249-252.
23. Mauro, A.; Ciccarelli, C.; De Cesaris, P.; Scoglio, A.; Bouche, M.; Molinaro, M.; Aquino, A.; Zani, B.M. PKCalpha-mediated ERK, JNK and p38 activation regulates the myogenic program in human rhabdomyosarcoma cells. J. Cell Sci., 2002, 115(Pt 18), 3587-3599.
24. Cai, H.; Smola, U.; Wixler, V.; Eisenmann-Tappe, I.; Diaz-Meco, M. T.; Moscat, J.; Rapp, U.; Cooper, G. M. Role of diacylglycerolregulated protein kinase C isotypes in growth factor activation of the Raf-1 protein kinase. Mol. Cell Biol., 1997, 17(2), 732-741.
25. Grossoni, V. C.; Falbo, K.B.; Kazanietz, M. G.; Kier Joffe, E. D.; Urtreger, A. J. Protein kinase C delta enhances proliferation and survival of murine mammary cells. Mol. Carcinog., 2007, 46(5), 381-390.
26. Lee, Y. J.; Soh, J. W.; Jeoung, D. I.; Cho, C. K.; Jhon, G. J.; Lee, S. J.; Lee, Y. S. PKC epsilon -mediated ERK1/2 activation involved in radiation-induced cell death in NIH3T3 cells. Biochim. Biophys. Acta, 2003, 1593(2-3), 219-229.
27. Monick, M. M.; Carter, A. B.; Flaherty, D. M.; Peterson, M. W.; Hunninghake, G.W. Protein kinase C zeta plays a central role in activation of the p42/44 mitogen-activated protein kinase by endotoxin in alveolar macrophages. J. Immunol., 2000, 165(8), 4632-4639.
28. Urtreger, A. J.; Grossoni, V. C.; Falbo, K. B.; Kazanietz, M. G.; Bal de Kier Joffe, E.D. Atypical protein kinase C-zeta modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells. Mol. Carcinog., 2005, 42(1), 29-39.
29. Zhong, M.; Lu, Z.; Foster, D. A. Downregulating PKC delta provides a PI3K/Akt-independent survival signal that overcomes apoptotic signals generated by c-Src overexpression. Oncogene, 2002, 21(7), 1071-1078.
30. Li, W.; Zhang, J.; Flechner, L.; Hyun, T.; Yam, A.; Franke, T. F.; Pierce, J.H. Protein kinase C-alpha overexpression stimulates Akt activity and suppresses apoptosis induced by interleukin 3 withdrawal. Oncogene, 1999, 18(47), 6564-6572.
31. Gliki, G.; Wheeler-Jones, C.; Zachary, I. Vascular endothelial growth factor induces protein kinase C (PKC)-dependent Akt/PKB activation and phosphatidylinositol 3'-kinase-mediates PKC delta phosphorylation: role of PKC in angiogenesis. Cell Biol. Int., 2002, 26(9), 751-759.
32. Zheng, W. H.; Kar, S.; Quirion, R. Stimulation of protein kinase C modulates insulin-like growth factor-1-induced akt activation in PC12 cells. J. Biol. Chem., 2000, 275(18), 13377-13385.
33. Mao, M.; Fang, X.; Lu, Y.; Lapushin, R.; Bast, R. C., Jr.; Mills, G. B. Inhibition of growth-factor-induced phosphorylation and activation of protein kinase B/Akt by atypical protein kinase C in breast cancer cells. Biochem. J., 2000, 352 Pt 2, 475-482.
34. Li, L.; Sampat, K.; Hu, N.; Zakari, J.; Yuspa, S. H. Protein kinase C negatively regulates Akt activity and modifies UVC-induced apoptosis in mouse keratinocytes. J. Biol. Chem., 2006, 281(6), 3237-3243.
35. Naugler, W. E.; Karin, M. NF-kappaB and cancer-identifying targets and mechanisms. Curr. Opin. Genet. Dev., 2008, 18(1), 19-26.
36. Saijo, K.; Mecklenbrauker, I.; Santana, A.; Leitger, M.; Schmedt, C.; Tarakhovsky, A. Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. J. Exp. Med., 2002, 195(12), 1647-1652.
37. Lin, X.; O'Mahony, A.; Mu, Y.; Geleziunas, R.; Greene, W.C. Protein kinase C-theta participates in NF-kappaB activation induced by CD3-CD28 costimulation through selective activation of IkappaB kinase beta. Mol. Cell. Biol., 2000, 20(8), 2933-2940.
38. Lu, Z. G.; Liu, H.; Yamaguchi, T.; Miki, Y.; Yoshida, K. Protein kinase Cdelta activates RelA/p65 and nuclear factor-kappaB signaling in response to tumor necrosis factor-alpha. Cancer Res., 2009, 69(14), 5927-5935.
39. Minhajuddin, M.; Bijli, K. M.; Fazal, F.; Sassano, A.; Nakayama, K. I.; Hay, N.; Platanias, L. C.; Rahman, A. Protein kinase C-delta and phosphatidylinositol 3-kinase/Akt activate mammalian target of rapamycin to modulate NF-kappaB activation and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells. J. Biol. Chem., 2009, 284(7), 4052-4061.
40. Satoh, A.; Gukovskaya, A. S.; Nieto, J. M.; Cheng, J. H.; Gukovsky, I.; Reeve, J. R., Jr.; Shimosegawa, T.; Pandol, S. J. PKCdelta and -epsilon regulate NF-kappaB activation induced by cholecystokinin and TNF-alpha in pancreatic acinar cells. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, 287(3), G582-591.
41. Brodie, C.; Blumberg, P. M. Regulation of cell apoptosis by protein kinase c delta. Apoptosis, 2003, 8(1), 19-27.
42. Kang, Y.; Park, J. S.; Kim, S. H.; Shin, Y. J.; Kim, W.; Joo, H. J.; Chun, J. S.; Kim, H. J.; Ha, M. J. Overexpression of protein kinase C delta represses expression of proliferin in NIH3T3 cells that regulates cell proliferation. Mol. Cell Biol. Res. Commun., 2000, 4(3), 181-187.
43. Mischak, H.; Goodnight, J. A.; Kolch, W.; Martiny-Baron, G.; Schaechtle, C.; Kazanietz, M. G.; Blumberg, P. M.; Pierce, J. H.; Mushinski, J. F. Overexpression of protein kinase C-delta and - epsilon in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J. Biol. Chem., 1993, 268(9), 6090-6096.
44. Brodie, C.; Kuperstein, I.; Acs, P.; Blumberg, P. M. Differential role of specific PKC isoforms in the proliferation of glial cells and the expression of the astrocytic markers GFAP and glutamine synthetase. Brain Res. Mol. Brain Res., 1998, 56(1-2), 108-117.
45. Harrington, E. O.; Loffler, J.; Nelson, P. R.; Kent, K. C.; Simons, M.; Ware, J. A. Enhancement of migration by protein kinase Calpha and inhibition of proliferation and cell cycle progression by protein kinase Cdelta in capillary endothelial cells. J. Biol. Chem., 1997, 272(11), 7390-7397.
46. Vucenik, I.; Ramakrishna, G.; Tantivejkul, K.; Anderson, L. M.; Ramljak, D. Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCdelta-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Breast Cancer Res. Treat., 2005, 91(1), 35-45.
47. Cerda, S. R.; Bissonnette, M.; Scaglione-Sewell, B.; Lyons, M. R.; Khare, S.; Mustafi, R.; Brasitus, T. A. PKC-delta inhibits anchorage- dependent and -independent growth, enhances differentiation, and increases apoptosis in CaCo-2 cells. Gastroenterology, 2001, 120(7), 1700-1712.
48. Tanaka, Y.; Gavrielides, M. V.; Mitsuuchi, Y.; Fujii, T.; Kazanietz, M. G. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J. Biol. Chem., 2003, 278(36), 33753-33762.
49. Liu, J.; Dai, Q.; Chen, J.; Durrant, D.; Freeman, A.; Liu, T.; Grossman, D.; Lee, R.M. Phospholipid scramblase 3 controls mitochondrial structure, function, and apoptotic response. Mol. Cancer Res., 2003, 1(12), 892-902.
50. Basu, A. Involvement of protein kinase C-delta in DNA damageinduced apoptosis. J. Cell Mol. Med., 2003, 7(4), 341-350.
51. McCracken, M. A.; Miraglia, L. J.; McKay, R. A.; Strobl, J. S. Protein kinase C delta is a prosurvival factor in human breast tumor cell lines. Mol. Cancer Ther., 2003, 2(3), 273-281.
52. Clark, A. S.; West, K. A.; Blumberg, P. M.; Dennis, P. A. Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCdelta promotes cellular survival and chemotherapeutic resistance. Cancer Res., 2003, 63(4), 780-786.
53. Basu, A.; Akkaraju, G. R. Regulation of caspase activation and cisdiamminedichloroplatinum(II)-induced cell death by protein kinase C. Biochemistry, 1999, 38(14), 4245-4251.
54. Regala, R. P.; Weems, C.; Jamieson, L.; Khoor, A.; Edell, E. S.; Lohse, C. M.; Fields, A. P. Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res., 2005, 65(19), 8905-8911.
55. Denning, M. F. Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms. Int. J. Biochem. Cell Biol., 2004, 36(7), 1141-1146.
56. Gavrielides, M. V.; Frijhoff, A. F.; Conti, C. J.; Kazanietz, M. G. Protein kinase C and prostate carcinogenesis: targeting the cell cycle and apoptotic mechanisms. Curr. Drug Targets, 2004, 5(5), 431-443.
57. Lee, S. A.; Karaszkiewicz, J. W.; Anderson, W.B. Elevated level of nuclear protein kinase C in multidrug-resistant MCF-7 human breast carcinoma cells. Cancer Res., 1992, 52(13), 3750-3759.
58. Ways, D. K.; Kukoly, C. A.; deVente, J.; Hooker, J. L.; Bryant, W. O.; Posekany, K. J.; Fletcher, D. J.; Cook, P. P.; Parker, P. J. 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, 1995, 95(4), 1906-1915.
59. Tonetti, D. A.; Chisamore, M. J.; Grdina, W.; Schurz, H.; Jordan, V. C. Stable transfection of protein kinase C alpha cDNA in hormone- dependent breast cancer cell lines. Br. J. Cancer, 2000, 83(6), 782-791.
60. Ali, A. S.; Ali, S.; El-Rayes, B. F.; Philip, P. A.; Sarkar, F. H. Exploitation of protein kinase C: a useful target for cancer therapy. Cancer Treat. Rev., 2009, 35(1), 1-8.
61. Juarez, J.; Clayman, G.; Nakajima, M.; Tanabe, K. K.; Saya, H.; Nicolson, G. L.; Boyd, D. Role and regulation of expression of 92- kDa type-IV collagenase (MMP-9) in 2 invasive squamous-cellcarcinoma cell lines of the oral cavity. Int. J. Cancer, 1993, 55(1), 10-18.
62. Aguirre-Ghiso, J. A.; Alonso, D. F.; Farias, E. F.; Bal de Kier Joffé, E. D. Overproduction of urokinase-type plasminogen activator is regulated by phospholipase D and protein kinase C-dependent pathways in murine mammary adenocarcinoma cells. Biochim. Biophys. Acta, 1997, 1356(2), 171-184.
63. Aguirre Ghiso, J. A.; Alonso, D. F.; Farias, E. F.; Gomez, D. E.; Bal de Kier Joff' E. D. Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. Eur. J. Biochem., 1999, 263(2), 295-304.
64. Egeblad, M.; Werb, Z. New functions for matrix metalloproteinases in cancer progression. Nat. Rev. Cancer, 2002, 2(3), 161-174.
65. Li, H.; Weinstein, I. B. Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells. Cancer Res., 2006, 66(23), 11399-11408.
66. Fujii, T.; Nakamura, A. M.; Yokoyama, G.; Yamaguchi, M.; Tayama, K.; Miwa, K.; Toh, U.; Kawamura, D.; Shirouzu, K.; Yamana, H.; Kuwano, M.; Tsuda, H. Antineoplaston induces G(1) arrest by PKCalpha and MAPK pathway in SKBR-3 breast cancer cells. Oncol. Rep., 2005, 14(2), 489-494.
67. Liu, J. F.; Crepin, M.; Liu, J. M.; Barritault, D.; Ledoux, D. FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway. Biochem. Biophys. Res. Commun., 2002, 293(4), 1174-1182.
68. Keshamouni, V. G.; Mattingly, R. R.; Reddy, K. B. Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. J. Biol. Chem., 2002, 277(25), 22558-22565.
69. Teicher, B. A. Protein kinase C as a therapeutic target. Clin. Cancer Res., 2006, 12(18), 5336-5345.
70. Scaglione-Sewell, B.; Abraham, C.; Bissonnette, M.; Skarosi, S. F.; Hart, J.; Davidson, N.O.; Wali, R. K.; Davis, B. H.; Sitrin, M.; Brasitus, T. A. Decreased PKC-alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells. Cancer Res., 1998, 58(5), 1074-1081.
71. Yu, W.; Murray, N. R.; Weems, C.; Chen, L.; Guo, H.; Ethridge, R.; Ceci, J. D.; Evers, B. M.; Thompson, E. A.; Fields, A. P. Role of cyclooxygenase 2 in protein kinase C beta II-mediated colon carcinogenesis. J. Biol. Chem., 2003, 278(13), 11167-11174.
72. Cerda, S. R.; Mustafi, R.; Little, H.; Cohen, G.; Khare, S.; Moore, C.; Majumder, P.; Bissonnette, M. Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators. Oncogene, 2006, 25(22), 3123-3138.
73. Mustafi, R.; Cerda, S.; Chumsangsri, A.; Fichera, A.; Bissonnette, M. Protein Kinase-zeta inhibits collagen I-dependent and anchorage- independent growth and enhances apoptosis of human Caco-2 cells. Mol. Cancer Res., 2006, 4(9), 683-694.
74. Louis, K.; Guerineau, N.; Fromigue, O.; Defamie, V.; Collazos, A.; Anglard, P.; Shipp, M. A.; Auberger, P.; Joubert, D.; Mari, B. Tumor cell-mediated induction of the stromal factor stromelysin-3 requires heterotypic cell contact-dependent activation of specific protein kinase C isoforms. J. Biol. Chem., 2005, 280(2), 1272-1283.
75. Ding, L.; Wang, H.; Lang, W.; Xiao, L. Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. J. Biol. Chem., 2002, 277(38), 35305-35313.
76. Regala, R. P.; Weems, C.; Jamieson, L.; Copland, J. A.; Thompson, E. A.; Fields, A. P. Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J. Biol. Chem., 2005, 280(35), 31109-31115.
77. Gonzalez-Guerrico, A. M.; Kazanietz, M. G. Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade: a key role for protein kinase C delta. J. Biol. Chem., 2005, 280(47), 38982-38991.
78. Guo, J.; Zhu, T.; Xiao, Z. X.; Chen, C. Y. Modulation of intracellular signaling pathways to induce apoptosis in prostate cancer cells. J. Biol. Chem., 2007, 282(33), 24364-24372.
79. Wu, D.; Foreman, T. L.; Gregory, C. W.; McJilton, M. A.; Wescott, G. G.; Ford, O. H.; Alvey, R. F.; Mohler, J. L.; Terrian, D. M. Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer. Cancer Res., 2002, 62(8), 2423-2429.
80. Mischak, H.; Pierce, J. H.; Goodnight, J.; Kazanietz, M. G.; Blumberg, P. M.; Mushinski, J. F. Phorbol ester-induced myeloid differentiation is mediated by protein kinase C-alpha and -delta and not by protein kinase C-beta II, -epsilon, -zeta, and -eta. J. Biol. Chem., 1993, 268(27), 20110-20115.
81. Powell, C. T.; Yin, L. Overexpression of PKCepsilon sensitizes LNCaP human prostate cancer cells to induction of apoptosis by bryostatin 1. Int. J. Cancer, 2006, 118(6), 1572-1576.
82. Wu, T. T.; Hsieh, Y. H.; Wu, C. C.; Hsieh, Y. S.; Huang, C. Y.; Liu, J. Y. Overexpression of protein kinase C alpha mRNA in human hepatocellular carcinoma: a potential marker of disease prognosis. Clin. Chim. Acta, 2007, 382(1-2), 54-58.
83. Aziz, M. H.; Manoharan, H. T.; Verma, A. K. Protein kinase C epsilon, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res., 2007, 67(3), 1385-1394.
84. D'Costa, A. M.; Robinson, J. K.; Maududi, T.; Chaturvedi, V.; Nickoloff, B. J.; Denning, M. F. The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas. Oncogene, 2006, 25(3), 378-386.
85. Datta, K.; Li, J.; Bhattacharya, R.; Gasparian, L.; Wang, E.; Mukhopadhyay, D. Protein kinase C zeta transactivates hypoxiainducible factor alpha by promoting its association with p300 in renal cancer. Cancer Res., 2004, 64(2), 456-462.
86. Brenner, W.; Farber, G.; Herget, T.; Wiesner, C.; Hengstler, J. G.; Thuroff, J. W. Protein kinase C eta is associated with progression of renal cell carcinoma (RCC). Anticancer Res., 2003, 23(5A), 4001-4006.
87. Brenner, W.; Greber, I.; Gudejko-Thiel, J.; Beitz, S.; Schneider, E.; Walenta, S.; Peters, K.; Unger, R.; Thuroff, J.W. Migration of renal carcinoma cells is dependent on protein kinase Cdelta via beta1 integrin and focal adhesion kinase. Int. J. Oncol., 2008, 32(5), 1125-1131.
88. Grossoni, V. C.; Falbo, K. B.; Mauro, L.V.; Krasnapolski, M. A.; Kazanietz, M. G.; Bal de Kier Joffe, E. D.; Urtreger, A. J. Protein kinase C delta inhibits the production of proteolytic enzymes in murine mammary cells. Clin. Exp. Metastasis, 2007, 24(7), 513-520.
89. Mauro, L.V.; Grossoni, V. C.; Urtreger, A. J.; Yang, C.; Colombo, L. L.; Morandi, A.; Pallotta, M. G.; Kazanietz, M. G.; Bal de Kier Joffe, E. D.; Puricelli, L. L. PKC Delta (PKCdelta) promotes tumoral progression of human ductal pancreatic cancer. Pancreas, 39(1), e31-41.
90. El-Rayes, B. F.; Ali, S.; Philip, P. A.; Sarkar, F. H. Protein kinase C: a target for therapy in pancreatic cancer. Pancreas, 2008, 36(4), 346-352.
91. Ni, H.; Ergin, M.; Tibudan, S. S.; Denning, M. F.; Izban, K. F.; Alkan, S. Protein kinase C-delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis. Br. J. Haematol., 2003, 121(6), 849-856.
92. Fine, R. L.; Patel, J.; Chabner, B. A. Phorbol esters induce multidrug resistance in human breast cancer cells. Proc. Natl. Acad. Sci. USA, 1988, 85(2), 582-586.
93. Lorenzo, P. S.; Dennis, P. A. Modulating protein kinase C (PKC) to increase the efficacy of chemotherapy: stepping into darkness. Drug Resist. Updat., 2003, 6(6), 329-339.
94. Ahmad, S.; Glazer, R. I. Expression of the antisense cDNA for protein kinase C alpha attenuates resistance in doxorubicinresistant MCF-7 breast carcinoma cells. Mol. Pharmacol., 1993, 43(6), 858-862.
95. Blobe, G. C.; Sachs, C. W.; Khan, W. A.; Fabbro, D.; Stabel, S.; Wetsel, W. C.; Obeid, L. M.; Fine, R. L.; Hannun, Y. A. Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. J. Biol. Chem., 1993, 268(1), 658-664.
96. Yu, G.; Ahmad, S.; Aquino, A.; Fairchild, C. R.; Trepel, J. B.; Ohno, S.; Suzuki, K.; Tsuruo, T.; Cowan, K. H.; Glazer, R. I. Transfection with protein kinase C alpha confers increased multidrug resistance to MCF-7 cells expressing P-glycoprotein. Cancer Commun., 1991, 3(6), 181-189.
97. Serova, M.; Ghoul, A.; Benhadji, K. A.; Cvitkovic, E.; Faivre, S.; Calvo, F.; Lokiec, F.; Raymond, E. Preclinical and clinical development of novel agents that target the protein kinase C family. Semin. Oncol., 2006, 33(4), 466-478.
98. Gollapudi, S.; Patel, K.; Jain, V.; Gupta, S. Protein kinase C isoforms in multidrug resistant P388/ADR cells: a possible role in daunorubicin transport. Cancer Lett, 1992, 62(1), 69-75.
99. Masanek, U.; Stammler, G.; Volm, M. Modulation of multidrug resistance in human ovarian cancer cell lines by inhibition of Pglycoprotein 170 and PKC isoenzymes with antisense oligonucleotides. J. Exp. Ther. Oncol., 2002, 2(1), 37-41.
100. Jimeno, A.; Rudek, M. A.; Purcell, T.; Laheru, D. A.; Messersmith, W. A.; Dancey, J.; Carducci, M. A.; Baker, S. D.; Hidalgo, M.; Donehower, R. C. Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors. Cancer Chemother. Pharmacol., 2008, 61(3), 423-433.
101. Seynaeve, C. M.; Kazanietz, M. G.; Blumberg, P. M.; Sausville, E. A.; Worland, P. J. Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol. Pharmacol., 1994, 45(6), 1207-1214.
102. Kondapaka, S. B.; Zarnowski, M.; Yver, D. R.; Sausville, E. A.; 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., 2004, 10(21), 7192-7198.
103. Hsueh, C. T.; Kelsen, D.; Schwartz, G. K. UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracilinduced apoptosis in a sequence-dependent manner. Clin. Cancer Res., 1998, 4(9), 2201-2206.
104. Bhonde, M. R.; Hanski, M. L.; Magrini, R.; Moorthy, D.; Muller, A.; Sausville, E. A.; Kohno, K.; Wiegand, P.; Daniel, P. T.; Zeitz, M.; Hanski, C. 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, 2005, 24(1), 148-156.
105. Martiny-Baron, G.; Fabbro, D. Classical PKC isoforms in cancer. Pharmacol. Res., 2007, 55(6), 477-486.
106. Mackay, H. J.; Twelves, C. J. Protein kinase C: a target for anticancer drugs? Endocr. Relat. Cancer, 2003, 10(3), 389-396.
107. Ganeshaguru, K.; Wickremasinghe, R. G.; Jones, D. T.; Gordon, M.; Hart, S. M.; Virchis, A. E.; Prentice, H. G.; Hoffbrand, A. V.; Man, A.; Champain, K.; Csermak, K.; Mehta, A. B. Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica, 2002, 87(2), 167-176.
108. Killion, J. J.; Beltran, P.; O'Brian, C. A.; Yoon, S. S.; Fan, D.; Wilson, M. R.; Fidler, I.J. The antitumor activity of doxorubicin against drug-resistant murine carcinoma is enhanced by oral administration of a synthetic staurosporine analogue, CGP 41251. Oncol. Res., 1995, 7(9), 453-459.
109. Fabbro, D.; Ruetz, S.; Bodis, S.; Pruschy, M.; Csermak, K.; Man, A.; Campochiaro, P.; Wood, J.; O'Reilly, T.; Meyer, T. PKC412--a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des., 2000, 15(1), 17-28.
110. Thavasu, P.; Propper, D.; McDonald, A.; Dobbs, N.; Ganesan, T.; Talbot, D.; Braybrook, J.; Caponigro, F.; Hutchison, C.; Twelves, C.; Man, A.; Fabbro, D.; Harris, A.; Balkwill, F. The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Res., 1999, 59(16), 3980-3984.
111. Monnerat, C.; Henriksson, R.; Le Chevalier, T.; Novello, S.; Berthaud, P.; Faivre, S.; Raymond, E. Phase I study of PKC412 (Nbenzoyl- staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with nonsmall- cell lung cancer. Ann. Oncol., 2004, 15(2), 316-323.
112. Utz, I.; Spitaler, M.; Rybczynska, M.; Ludescher, C.; Hilbe, W.; Regenass, U.; Grunicke, H.; Hofmann, J. Reversal of multidrug resistance by the staurosporine derivatives CGP 41251 and CGP 42700. Int. J. Cancer, 1998, 77(1), 64-69.
113. Faul, M. M.; Gillig, J. R.; Jirousek, M. R.; Ballas, L. M.; Schotten, T.; Kahl, A.; Mohr, M. Acyclic N-(azacycloalkyl) bisindolylmaleimides: isozyme selective inhibitors of PKCbeta. Bioorg. Med. Chem. Lett., 2003, 13(11), 1857-1859.
114. Rademaker-Lakhai, J. M.; Beerepoot, L. V.; Mehra, N.; Radema, S. A.; van Maanen, R.; Vermaat, J. S.; Witteveen, E. O.; Visseren- Grul, C. M.; Musib, L.; Enas, N.; van Hal, G.; Beijnen, J. H.; Schellens, J. H.; Voest, E. E. Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer. Clin. Cancer Res., 2007, 13(15 Pt 1), 4474-4481.
115. Teicher, B.A.; Alvarez, E.; Menon, K.; Esterman, M. A.; Considine, E.; Shih, C.; Faul, M. M. Antiangiogenic effects of a protein kinase Cbeta-selective small molecule. Cancer Chemother. Pharmacol., 2002, 49(1), 69-77.
116. Rizvi, M. A.; Ghias, K.; Davies, K. M.; Ma, C.; Weinberg, F.; Munshi, H. G.; Krett, N. L.; Rosen, S. T. Enzastaurin (LY317615), a protein kinase Cbeta inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines. Mol. Cancer Ther., 2006, 5(7), 1783-1789.
117. Podar, K.; Raab, M. S.; Zhang, J.; McMillin, D.; Breitkreutz, I.; Tai, Y. T.; Lin, B.K.; Munshi, N.; Hideshima, T.; Chauhan, D.; Anderson, K.C. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl). Blood, 2007, 109(4), 1669-1677.
118. Teicher, B. A.; Menon, K.; Alvarez, E.; Galbreath, E.; Shih, C.; Faul, M. M. Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human HT-29 colon carcinoma and human CaKi1 renal cell carcinoma xenografts. Anticancer Res., 2001, 21(5), 3175-3184.
119. Hofmann, J. Modulation of protein kinase C in antitumor treatment. Rev. Physiol. Biochem. Pharmacol., 2001, 142(), 1-96.
120. Pavlick, A. C.; Wu, J.; Roberts, J.; Rosenthal, M.A.; Hamilton, A.; Wadler, S.; Farrell, K.; Carr, M.; Fry, D.; Murgo, A. J.; Oratz, R.; Hochster, H.; Liebes, L.; Muggia, F. Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors. Cancer Chemother. Pharmacol., 2009, 64(4), 803-810.
121. Zonder, J. A.; Shields, A. F.; Zalupski, M.; Chaplen, R.; Heilbrun, L. K.; Arlauskas, P.; Philip, P. A. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res., 2001, 7(1), 38-42.
122. Garzotto, M.; White-Jones, M.; Jiang, Y.; Ehleiter, D.; Liao, W.C.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R. 12-Otetradecanoylphorbol- 13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Res., 1998, 58(10), 2260-2264.
123. Zheng, X.; Chang, R. L.; Cui, X. X.; Kelly, K. A.; Shih, W. J.; Lin, Y.; Strair, R.; Suh, J.; Han, Z. T.; Rabson, A.; Conney, A. H. Synergistic effects of clinically achievable concentrations of 12-Otetradecanoylphorbol- 13-acetate in combination with all-trans retinoic acid, 1alpha,25-dihydroxyvitamin D3, and sodium butyrate on differentiation in HL-60 cells. Oncol. Res., 2000, 12(9-10), 419-427.
124. Strair, R. K.; Schaar, D.; Goodell, L.; Aisner, J.; Chin, K. V.; Eid, J.; Senzon, R.; Cui, X. X.; Han, Z. T.; Knox, B.; Rabson, A. B.; Chang, R.; Conney, A. Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate. Clin. Cancer Res., 2002, 8(8), 2512-2518.
125. Choi, S. H.; Hyman, T.; Blumberg, P. M. Differential effect of bryostatin 1 and phorbol 12-myristate 13-acetate on HOP-92 cell proliferation is mediated by down-regulation of protein kinase Cdelta. Cancer Res., 2006, 66(14), 7261-7269.
126. Griner, E.M.; Kazanietz, M.G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer, 2007, 7(4), 281-294.
127. Rao, S.; Watkins, D.; Cunningham, D.; Dunlop, D.; Johnson, P.; Selby, P.; Hancock, B.W.; Fegan, C.; Culligan, D.; Schey, S.; Morris, T. C.; Lissitchkov, T.; Oliver, J. W.; Holmlund, J. T. 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., 2004, 15(9), 1413-1418.
128. Li, K.; Zhang, J. ISIS-3521. Isis Pharmaceuticals. Curr. Opin. Investig. Drugs, 2001, 2(10), 1454-1461.
129. Advani, R.; Peethambaram, P.; Lum, B. L.; Fisher, G. A.; Hartmann, L.; Long, H. J.; Halsey, J.; Holmlund, J. T.; Dorr, A.; Sikic, B. I. 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, 2004, 100(2), 321-326.
130. Leslie, W. T.; Bonomi, P.D. Novel treatments in non-small cell lung cancer. Hematol. Oncol. Clin. North Am., 2004, 18(1), 245-267.
131. Schwartz, G. K.; Ward, D.; Saltz, L.; Casper, E. S.; Spiess, T.; Mullen, E.; Woodworth, J.; Venuti, R.; Zervos, P.; Storniolo, A. M.; Kelsen, D. P. A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin. Cancer Res., 1997, 3(4), 537-543.
132. Bergan, R. C.; Reed, E.; Myers, C. E.; Headlee, D.; Brawley, O.; Cho, H. K.; Figg, W. D.; Tompkins, A.; Linehan, W. M.; Kohler, D.; Steinberg, S. M.; Blagosklonny, M. V. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin. Cancer Res., 1999, 5(9), 2366-2373.