Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720

Transplant International

Volumn 23, Issue 5, 2010, Pages 543-552

  Weckbecker, Gisbert ^a   Pally, Charles ^a   Beerli, Christian ^a   Burkhart, Christoph ^a   Wieczorek, Grazyna ^a   Metzler, Barbara ^a   Morris, Randall E ^a   Wagner, Juergen ^a   Bruns, Christian ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

AEB071; Animal; Immunosuppressant; Nonclinical; Protein kinase C inhibitor; Sotrastaurin; Transplantation

Indexed keywords

CYCLOSPORIN; CYCLOSPORIN A; EVEROLIMUS; FINGOLIMOD; SOTRASTAURIN; ENZYME INHIBITOR; IMMUNOSUPPRESSIVE AGENT; PROPANEDIOL DERIVATIVE; PROTEIN KINASE C; PYRROLE DERIVATIVE; QUINAZOLINE DERIVATIVE; RAPAMYCIN; SPHINGOSINE;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG CLEARANCE; GRAFT REJECTION; GRAFT SURVIVAL; HAPLOTYPE; HEART GRAFT; IMMUNOSUPPRESSIVE TREATMENT; LYMPH NODE; MALE; MONOTHERAPY; NONHUMAN; PRIORITY JOURNAL; RAT; SURVIVAL TIME; T LYMPHOCYTE ACTIVATION; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG COMBINATION; DRUG INTERACTION; HEART TRANSPLANTATION; LEWIS RAT; PROCEDURES; WISTAR RAT;

ANIMALS; CYCLOSPORINE; DRUG INTERACTIONS; DRUG THERAPY, COMBINATION; ENZYME INHIBITORS; HEART TRANSPLANTATION; IMMUNOSUPPRESSIVE AGENTS; MALE; PROPYLENE GLYCOLS; PROTEIN KINASE C; PYRROLES; QUINAZOLINES; RATS; RATS, INBRED LEW; RATS, WISTAR; SIROLIMUS; SPHINGOSINE;

EID: 77950681760     PISSN: 09340874     EISSN: 14322277     Source Type: Journal    
DOI: 10.1111/j.1432-2277.2009.01015.x     Document Type: Article

References (32)

1. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004 351 : 2715.
2. Lechler R, Sykes M, Thomson AW, Turka LA. Organ Transplantation - how much of the promise has been realized? Nat Med 2005 11 : 605. (Pubitemid 40868300)
3. Hall BM. Cells mediating allograft rejection. Transplantation 1991 51 : 1141.
4. Kane LP, Lin J, Weiss A. Signal transduction by the TCR for antigen. Curr Opin Urol 2000 12 : 242. (Pubitemid 30240532)
5. Parker PJ, Murray-Rust J. PKC at a glance. J Cell Science 2004 117 : 131. (Pubitemid 38128893)
6. Tan S-L, Parker PJ. Emerging and diverse roles of protein kinase C in immune cell signaling. Biochem J 2003 376 : 545.
7. Salonen T, Sareila O, Jalonen U, Kankaanranta H, Tuominen R, Moilanen E. Inhibition of classical PKC isoenzymes downregulates STAT1 activation and iNOS expression in LPS-treated murine J774 macrophages. Brit J Pharmacol 2006 147 : 790.
8. Humphries MJ, Limesand KH, Schneider JC, Nakayama KI, Anderson SM, Reyland ME. Suppression of apoptosis in the protein kinase Cδ-null mouse in vivo. J Biol Chem 2006 281 : 9728.
9. Klecha AJ, Genaro AM, Gorelik G, et al. Integrative study of hypothalamus-pituitary-thyroid-immune system interaction: thyroid hormone-mediated modulation of lymphocyte activity through the protein kinase C signaling pathway. J Endocrinol 2006 189 : 45.
10. Sumoza-Toledo A, Eaton AD, Sarukhan A. Regulatory T cells inhibit protein kinase Cθ recruitment to the immune synapse of naive T cells with the same antigen specificity. J Immunol 2006 176 : 5779.
11. + T cell survival by up-regulating Bcl-xL. J Immunol 2006 176 : 6709. (Pubitemid 43787854)
12. von Essen M, Nielsen MW, Bonefeld CM, et al. Protein kinase C (PKC)α and PKCθ are the major PKC isotypes involved in TCR down-regulation. J Immunol 2006 176 : 7502.
13. + T lymphocytes. Blood 2006 107 : 4841. (Pubitemid 43882636)
14. Pardo OE, Wellbrock C, Khanzada UK, et al. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCη, B-Raf and S6K2. EMBO J 2006 25 : 3078. (Pubitemid 44106760)
15. Hayashi K, Altman A. Filamin A is required for T cell activation mediated by protein kinase C-theta. J Immunol 2006 177 : 1721. (Pubitemid 44092508)
16. Healy AM, Izmailova E, Fitzgerald M, et al. PKC-theta deficient mice are protected from Th1-dependent antigen-induced arthritis. J Immunol 2006 177 : 1886. (Pubitemid 44092528)
17. Baier G. The PKC gene module: molecular biosystematics to resolve its T cell functions. J Immunol. Reviews. 2003 192 : 64.
18. Guo B, Su TT, Rawlings DJ. Protein kinase C family functions in B-cell activation. Curr Opin Immunol 2004 16 : 367.
19. Pfeifhofer C, Gruber T, Letschka T, et al. Defective IgG2a/2b class switching in PKCα-/- mice. J Immunol 2006 176 : 6004.
20. Leitges M, Schmedt C, Guinamard R, et al. Immunodeficiency in protein kinase C beta-deficient mice. Science 1996 273 : 788.
21. Altman A, Isakov N, Baier G. Protein kinase C θ: a new essential superstar on the T-cell stage. Immunol Today 2000 21 : 567.
22. Sun Z, Arendt CW, Ellmeier W, et al. PKC-θ is required for TCR-induced NFκB activation in mature but not immature T lymphocytes. Nature 2000 404 : 402.
23. 2+mobilization and NFAT cell activation in primary mouse T cells. J Exp Med 2003 197 : 1525.
24. Dumont FJ. Immunosuppressive strategies for prevention of transplant rejection. Exp Opin Ther Patents 2001 11 : 377.
25. Hu H. Recent discovery and development of selective protein kinase C inhibitors. DDT 1996 1 : 438.
26. Wilkinson SE, Nixon JS. T-cell signal transduction and the role of protein kinase C. Cell Mol Life Sci 1998 54 : 112.
27. Evenou JP, Wagner J, Zenke G, Brinkmann V, Wagner K, Kovarik J. The potent protein kinase C selective inhibitor AEB071 (Sotrastaurin) represents a new class of immunosuppressive agents affecting early T cell activation. J Pharmacol Exp Ther 2009 330 : 792.
28. Weckbecker G, Bruns C, Fischer KD, et al. Strongly reduced alloreactivity and long-term survival times of cardiac allografts in Vav1- and Vav1/Vav2-knockout mice. Transplant Intl 2007 20 : 353.
29. Rolstad B. The popliteal lymph node graft-versus-host (GvH) reaction in the rat: a useful model for studying cell interactions in the immune response? Immunol Rev 1985 88 : 153.
30. Ono K, Lindsey ES. Improved technique of heart transplantation in the rat. J Thorac Cardiovasc Surg 1969 57 : 225.
31. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2006 24 : 1710.
32. Skvara H, Dawid M, Kleyn E, et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J Clin Invest 2008 118 : 3151.