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Protein kinase C inhibitors

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Abstract

Protein kinase C (PKC) is a family of serine-threonine protein kinases that are involved in signal transduction pathways that regulate growth factor response, proliferation, and apoptosis. Its central role in these processes, which are closely involved in tumor initiation, progression, and response to antitumor agents, makes it an attractive therapeutic target in cancer. Despite initial activity seen in melanoma (bryostatin and UCN-01), non-Hodgkin’s lymphoma (ISIS 3521, bryostatin, and UCN-01), and ovarian carcinoma (ISIS 3521 and bryostatin) in phase I studies, single-agent activity in those phase II studies reported to date has been limited. Preclinical data highlight a role for PKC in modulation of drug resistance and synergy with conventional cytotoxic drugs. A randomized phase III study of ISIS 3521 in combination with carboplatin and paclitaxel, compared with chemotherapy alone, in advanced non-small-cell lung cancer is underway. This paper reviews the rationale for using PKC inhibitors in cancer therapy, the challenges for clinical trial design, and the recent clinical experience with modulators of PKC activity.

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References and Recommended Reading

  1. Cartee L, Kucera GL: Protein kinase C modulation and anticancer drug response. Cancer Invest 2000, 18:731–739.

    PubMed  CAS  Google Scholar 

  2. Goekjian PG, Jirousek MR: Protein kinase C in the treatment of disease: signal transduction pathways, inhibitors, and agents in development. Curr Med Chem 1999, 6:877–903. A complementary review of PKC inhibitors, including their role in diseases other than cancer.

    PubMed  CAS  Google Scholar 

  3. Castagna M, Takai Y, Kaibachi K, et al.: Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 1982, 257:7847–7851.

    PubMed  CAS  Google Scholar 

  4. Nishizuka Y: The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 1984, 308:693–698.

    Article  PubMed  CAS  Google Scholar 

  5. Jarvis WD, Turner AJ, Povirk LF, et al.: Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C. Cancer Res 1994, 54:1707–1714.

    PubMed  CAS  Google Scholar 

  6. Hofmann J: Modulation of protein kinase C in antitumor treatment. Rev Physiol Biochem Pharmacol 2001, 142:1–96. A comprehensive review of the preclinical data concerning PKC as a target in cancer. The roles of individual isoenzymes are discussed in detail.

    PubMed  CAS  Google Scholar 

  7. Leirdal M, Sioud M: Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glioma cells. Br J Cancer 1999, 80:1558–1564.

    Article  PubMed  CAS  Google Scholar 

  8. Li H, Zhao L, Yang Z, et al.: Telomerase is controlled by protein kinase Calpha in human breast cancer cells. J Biol Chem 1998, 273:33436–33442.

    Article  PubMed  CAS  Google Scholar 

  9. Ku WC, Cheng AJ, Wang TC: Inhibition of telomerase activity by PKC inhibitors in human nasopharyngeal cancer cells in culture. Biochem Biophys Res Commun 1997, 241:730–736.

    Article  PubMed  CAS  Google Scholar 

  10. O’Brian CA, Ward NE: Biology of the protein kinase C family. Cancer Metastasis Rev 1989, 8:199–214.

    Article  PubMed  CAS  Google Scholar 

  11. Monks A, Harris ED, Vaigro-Wolff A, et al.: UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. Invest New Drugs 2000, 18:95–107.

    Article  PubMed  CAS  Google Scholar 

  12. Fabbro D, Ruetz S, Bodis S, et al.: PKC412: a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des 2000, 15:17–28.

    PubMed  CAS  Google Scholar 

  13. Fine RL, Chambers TC, Sachs CW: P-glycoprotein, multidrug resistance and protein kinase C. Stem Cells 1996, 14:47–55.

    Article  PubMed  CAS  Google Scholar 

  14. Budworth J, Gant TW, Gescher A: Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells. Br J Cancer 1997, 75:1330–1335.

    PubMed  CAS  Google Scholar 

  15. Ahmad S, Glazer RI: Expression of the antisense cDNA for protein kinase C alpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells. Mol Pharmacol 1993, 43:858–862.

    PubMed  CAS  Google Scholar 

  16. Yang JM, Chin KV, Hait WN: Interaction of P-glycoprotein with protein kinase C in human multidrug resistant carcinoma cells. Cancer Res 1996, 56:3490–3494.

    PubMed  CAS  Google Scholar 

  17. Beltran PJ, Fan D, Fidler IJ, et al.: Chemosensitization of cancer cells by the staurosporine derivative CGP 41251 in association with decreased P-glycoprotein phosphorylation. Biochem Pharmacol 1997, 53:245–247.

    Article  PubMed  CAS  Google Scholar 

  18. Goodfellow HR, Sardini A, Ruetz S, et al.: Protein kinase C-mediated phosphorylation does not regulate drug transport by the human multidrug resistance P-glycoprotein. J Biol Chem 1996, 271:13668–13674.

    Article  PubMed  CAS  Google Scholar 

  19. Chaudhary PM, Roninson IB: Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists. Oncol Res 1992, 4:281–290.

    PubMed  CAS  Google Scholar 

  20. Gill PK, Gescher A, Gant TW: Regulation of MDR1 promoter activity in human breast carcinoma cells by protein kinase C isozymes alpha and theta. Eur J Biochem 2001, 268:4151–4157.

    Article  PubMed  CAS  Google Scholar 

  21. Blagosklonny MV, Schulte T, Nguyen P, et al.: Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res 1996, 56:1851–1854.

    PubMed  CAS  Google Scholar 

  22. Livneh E, Fishman DD: Linking protein kinase C to cell-cycle control. Eur J Biochem 1997, 248:1–9.

    Article  PubMed  CAS  Google Scholar 

  23. Sausville EA, Arbuck SG, Messmann R, et al.: Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol 2001, 19:2319–2333. This report is from the only clinical study to attempt to demonstrate target inhibition in cells derived from tissue other than PBMNCs. UCN-01 is shown to inhibit phosphorylation of adducin, a PKC target, in mononuclear cells derived from a malignant pleural effusion and bone marrow. Plasma from UCN-01-treated patients is also shown to affect G2 checkpoint function in an ex vivo assay with irradiated MCF-7 cells.

    PubMed  CAS  Google Scholar 

  24. Thavasu P, Propper D, McDonald A, et al.: The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Res 1999, 59:3980–3984.

    PubMed  CAS  Google Scholar 

  25. Philip PA, Rea D, Thavasu P, et al.: Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor alpha induction in vivo. The Cancer Research Campaign Phase I Committee. J Natl Cancer Inst 1993, 85:1812–1818.

    Article  PubMed  CAS  Google Scholar 

  26. Jayson GC, Crowther D, Prendiville J, et al.: A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion. Br J Cancer 1995, 72:461–468.

    PubMed  CAS  Google Scholar 

  27. Scheid C, Prendivlle J, Jayson G, et al.: Immunomodulation in patients receiving intravenous bryostatin 1 in a phase I clinical study: comparison with effects of Bryostatin 1 on lymphocyte function in vitro. Cancer Immunol Immunother 1994, 39:223–230.

    PubMed  CAS  Google Scholar 

  28. Tamaoki T: Use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors. Methods Enzymol 1991, 201:340–347.

    Article  PubMed  CAS  Google Scholar 

  29. Seynaeve CM, Kazanietz MG, Blumberg PM, et al.: Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol Pharmacol 1994, 45:1207–1214.

    PubMed  CAS  Google Scholar 

  30. Shao RG, Shimizu T, Pommier Y: 7-Hydroxystaurosporine (UCN-01) induces apoptosis in human colon carcinoma and leukemia cells independently of p53. Exp Cell Res 1997, 234:388–397.

    Article  PubMed  CAS  Google Scholar 

  31. Wang Q, Fan S, Eastman A, et al.: UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 1996, 88:956–965.

    Article  PubMed  CAS  Google Scholar 

  32. Wang Q, Worland PJ, Clark JL, et al.: Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Differ 1995, 6:927–936.

    PubMed  CAS  Google Scholar 

  33. Busby EC, Leistritz DF, Abraham RT, et al.: The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res 2000, 60:2108–2112. UCN-01 is shown to inhibit hChk1 and cTAK1, which control cdc25C phosphorylation and G2 checkpoint control, at concentrations at which UCN-01 increases sensitivity to DNA damaging agents. Its action as a modulator of cdk1 activity may be a more important mechanism of action than inhibition of PKC.

    PubMed  CAS  Google Scholar 

  34. Senderowicz AM: Small molecule modulators of cyclin-dependent kinases for cancer therapy. Oncogene 2000, 19:6600–6666.

    Article  PubMed  CAS  Google Scholar 

  35. Kurata N, Kuwabara T, Tanii H, et al.: Pharmacokinetics and pharmacodynamics of a novel protein kinase inhibitor, UCN-01. Cancer Chemother Pharmacol 1999, 44:12–18.

    Article  PubMed  CAS  Google Scholar 

  36. Fuse E, Tanii H, Takai K, et al.: Altered pharmacokinetics of a novel anticancer drug, UCN-01, caused by specific high affinity binding to alpha1-acid glycoprotein in humans. Cancer Res 1999, 59:1054–1060.

    PubMed  CAS  Google Scholar 

  37. Hsueh CT, Wu YC, Schwartz GK: UCN-01 suppresses E2F-1 mediated by ubiquitin-proteasome-dependent degradation. Clin Cancer Res 2001, 7:669–674.

    PubMed  CAS  Google Scholar 

  38. Shah MA, Kemeny N, Kelsen D, et al.: A phaseI/pharmacologic study of UCN-01 in combination with 5-fluorouracil in patients with advanced solid tumours [abstract]. Proc ASCO 2001, 20:3135.

    Google Scholar 

  39. Propper DJ, McDonald AC, Man A, et al.: Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol 2001, 19:1485–1492.

    PubMed  CAS  Google Scholar 

  40. Garcia-Carbonero R, Eder JP, Clark JW, et al.: Phase I and pharmacokinetic study of PKC412 combined with 5-fluorouracil in patients with advanced solid malignancies [abstract]. Proc ASCO 2001, 20:329.

    Google Scholar 

  41. Fischer T, Beck V, Petersen B, et al.: A phase I and pharmacokinetic trial of PKC412, an inhibitor of protein kinase C, in combination with taxol and carboplatin in patients with advanced NSCLC [abstract]. Proc ASCO 2001, 20:1322.

    Google Scholar 

  42. Tamm IB, Dorken B, Hartmann G: Antisense therapy in oncology: new hope for an old idea? Lancet 2001, 358:489–497. A useful review of the antisense strategy in anticancer therapy. The authors include ISIS 3521 and discuss the potential benefits and limitations of the approach.

    Article  PubMed  CAS  Google Scholar 

  43. Dean NM, McKay R: Inhibition of protein kinase C-alpha expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc Natl Acad Sci U S A 1994, 91:11762–11766.

    Article  PubMed  CAS  Google Scholar 

  44. Yuen AR, Halsey J, Fisher GA, 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 1999, 5:3357–3363.

    PubMed  CAS  Google Scholar 

  45. Nemunaitis J, Holmlund JT, Kraynak M, et al.: Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 1999, 17:3586–3595.

    PubMed  CAS  Google Scholar 

  46. Portnow J, Eller S, Stecker K, et al.: The distribution of an antisense oligonucleotide directed against PKCa (ISIS3521) in rats with brain tumours [abstract]. Proc ASCO 2000, 19:660.

    Google Scholar 

  47. Schwartz GK, Ward D, Saltz L, et al.: A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin Cancer Res 1997, 3:537–543.

    PubMed  CAS  Google Scholar 

  48. Ferry DR, Smith A, Malkhandi J, et al.: Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 1996, 2:659–668.

    PubMed  CAS  Google Scholar 

  49. Mulholland PJ, Ferry DR, Anderson D, et al.: Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin. Ann Oncol 2001, 12:245–248.

    Article  PubMed  CAS  Google Scholar 

  50. da RochaAB, Mans DR, Bernard EA, 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 1999, 35:833–839.

    Article  PubMed  Google Scholar 

  51. Couldwell WT, Hinton DR, Sarnack AA, et al.: Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 1996, 2:619–622.

    PubMed  CAS  Google Scholar 

  52. Ben Arush MW, Postovsky S, Godsher D, et al.: Clinical and radiographic response in three children with recurrent malignant cerebral tumors with high-dose tamoxifen. Pediatr Hematol Oncol 1999, 16:245–250.

    Article  PubMed  Google Scholar 

  53. Walter AW, Gajjar A, Reardon DA, et al.: Tamoxifen and carboplatin for children with low-grade gliomas: a pilot study at St. Jude Children’s Research Hospital. J Pediatr Hematol Oncol 2000, 22:247–251.

    Article  PubMed  CAS  Google Scholar 

  54. Lara PN: Activity of high-dose toremifene plus cisplatin in platinum treated non-small cell lung cancer. Cancer Chemother Pharmacol 2001, 48:22–28.

    Article  PubMed  CAS  Google Scholar 

  55. Bergan RC, Reed E, Myers CE, et al.: A phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin Cancer Res 1999, 5:2366–2373.

    PubMed  CAS  Google Scholar 

  56. Smorenburg CH, Seynaeve C, Bontenbal M, et al.: Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Anticancer Drugs 2000, 11:825–828.

    Article  PubMed  CAS  Google Scholar 

  57. Prendiville J, Crowther D, Thatcher N, et al.: A phase I study of intravenous bryostatin 1 in patients with advanced cancer. Br J Cancer 1993, 68:418–424.

    PubMed  CAS  Google Scholar 

  58. Varterasian ML, Mohammad RM, Eilender DS, et al.: Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. J Clin Oncol 1998, 16:56–62.

    PubMed  CAS  Google Scholar 

  59. Grant S, Roberts J, Poplin E, et al.: Phase Ib trial of bryostatin 1 in patients with refractory malignancies. Clin Cancer Res 1998, 4:611–618.

    PubMed  CAS  Google Scholar 

  60. Weitman S, Langevin AM, Berkow RL, et al.: A phase I trial of bryostatin-1 in children with refractory solid tumors: a Pediatric Oncology Group study. Clin Cancer Res 1999, 5:2344–2348.

    PubMed  CAS  Google Scholar 

  61. Propper DJ, Macaulay V, O’Byrne KJ, et al.: A phase II study of bryostatin 1 in metastatic malignant melanoma. Br J Cancer 1998, 78:1337–1341.

    PubMed  CAS  Google Scholar 

  62. Gonzalez R, Ebbinghaus S, Henthorn TK, et al.: Treatment of patients with metastatic melanoma with bryostatin-1: a phase II study. Melanoma Res 1999, 9:599–606.

    Article  PubMed  CAS  Google Scholar 

  63. Bedikian AY, Plager C, Stewart JR, et al.: Phase II evaluation of bryostatin-1 in metastatic melanoma. Melanoma Res 2001, 11:183–188.

    Article  PubMed  CAS  Google Scholar 

  64. Blackhall FH, Ranson M, Radford JA, et al.: A phase II trial of bryostatin 1 in patients with non-Hodgkin’s lymphoma. Br J Cancer 2001, 84:465–469.

    Article  PubMed  CAS  Google Scholar 

  65. Varterasian ML, Mohammad RM, Shurafa MS, et al.: Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Clin Cancer Res 2000, 6:825–828.

    PubMed  CAS  Google Scholar 

  66. Zonder JA, Shields AF, Zalupski M, et al.: A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin Cancer Res 2001, 7:38–42.

    PubMed  CAS  Google Scholar 

  67. Pagliaro L, Daliani D, Amato R, et al.: A phase II trial of bryostatin-1 for patients with metastatic renal cell carcinoma. Cancer 2000, 89:615–618.

    Article  PubMed  CAS  Google Scholar 

  68. Tozer S, Burdette-Radoux K, Belanger ML, et al.: NCIC randomized phase II study of two schedules of bryostatin 1 (NSC39555) in patients with advanced malignant melanoma [abstract]. Proc ASCO 1999, 18:2052.

    Google Scholar 

  69. Haas NB, Smith M, Lewis N, et al.: A phase II trial of weekly bryostatin (Bryo-1) in metastatic renal cell carcinoma (RCC) [abstract]. Proc ASCO 2001, 20:764.

    Google Scholar 

  70. Rosenthal A, Oratz R, Liebes L, et al.: Phase I study of bryostatin-1 (NSC 339555) and cisplatin in advanced malignancies [abstract]. Proc ASCO 1999, 18:873.

    Google Scholar 

  71. Bangalore NS, Baidas S, Bhargava P, et al.: Phase I study of bryostatin-1 and cisplatin in patients with advanced cancer [abstract]. Proc ASCO 2000, 19:794.

    Google Scholar 

  72. Lenz HJ, Gupta M, Xiong YP, et al.: Phase I study of bryostatin-1 and cisplatin (CDDP) [abstract]. Proc ASCO 2000, 19:795.

    Google Scholar 

  73. Pavlick AC, Hamilton A, Liebes L, et al.: Bryostatin 1 and cisplatin: a phase I and pharmacodynamic study [abstract]. Proc ASCO 2001, 20:328.

    Google Scholar 

  74. Kaubisch A, Kelsen DP, Saltz L, et al.: A phase I trial of weekly sequential broystatin-1 (BRYO) and paclitaxel in patients with advanced solid tumors [abstract]. Proc ASCO 1999, 18:639.

    Google Scholar 

  75. Ilson D, Shah M, O’Reilly E, et al.: A phase II trial of weekly one hour paclitaxel followed by bryostatin-1 in patients with advanced esophageal cancer: an active new drug combination [abstract]. Proc ASCO 2001, 20:633.

    Google Scholar 

  76. Charoentum C, Mauer AM, Gajewski TF, et al.: Phase II study of bryostatin-1 in combination with paclitaxel for advanced non-small cell lung cancer (NSCLC) [abstract]. Proc ASCO 2001, 20:2834.

    Google Scholar 

  77. Kaubish A, Kelsen DP, Saltz L: Phase I trial of weekly sequential bryostatin-1, cisplatin, and paclitaxel in patients with advanced solic tumors [abstract]. Proc ASCO 2000, 19:900.

    Google Scholar 

  78. Dowlati A, Robertson K, Ksenich P, et al.: Phase I trial of combination bryostatin-1 and vincristine in B-cell malignancies [abstract]. Proc ASCO 2000, 19:837.

    Google Scholar 

  79. Advani R, Fisher GA, Grant P, et al.: A phase I trial of an antisence oligonucleotide targeted to protein kinase C-a delivered as a 24-hour continuous infusion [abstract]. Proc ASCO 1999, 18:609.

    Google Scholar 

  80. Alavi JB, Grossman SA, Supko J, et al.: Efficacy, toxicity, and pharmacology of an antisense oligonucleotide directed against protein kinase C-? (ISIS 3521) delivered as a 21 day continuous intravenous infusion in patients with recurrent high grade astrocytomas (HGA) [abstract]. Proc ASCO 2000, 19:647.

    Google Scholar 

  81. Gradishar WJ, O’Neill A, Cobleigh M, et al.: A phase II trial with antisense oligonucleotide ISIS 3521/Cgp 64128a in patients with metastatic breast cancer (MBC: ECOG trial 3197 [abstract]. Proc ASCO 2001, 20:171.

    Google Scholar 

  82. Yuen Y, Halsey J, Fisher G, et al.: Phase I/II trial of ISIS 3521, an antisense inhibitor of PKC-alpha, with carboplatin and paclitaxel in non-small cell lung cancer [abstract]. Proc ASCO 2001, 20:1234.

    Google Scholar 

  83. Mani S, Shulman K, Kunkel R, et al.: Phase I trial of protein kinase -C a antisense oligonucleotide (ISIS 3521; ISI 641A) with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with advanced cancer [abstract]. Proc ASCO 1999, 18:608.

    Google Scholar 

  84. Caponigro F, French RC, Kaye SB: Protein kinase C: a worthwhile target for anticancer drugs? Anticancer Drugs 1997, 8:26–33.

    Article  PubMed  CAS  Google Scholar 

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  1. CRC Department of Medical Oncology, Royal Marsden Hospital, SM2 5NG, Sutton, Surrey, UK

    Helen C. Swannie MRCP & Stanley B. Kaye MD, FRCP

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  1. Helen C. Swannie MRCP
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  2. Stanley B. Kaye MD, FRCP
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Swannie, H.C., Kaye, S.B. Protein kinase C inhibitors. Curr Oncol Rep 4, 37–46 (2002). https://doi.org/10.1007/s11912-002-0046-7

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