The oral protein-kinase C β inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines

Leukemia and Lymphoma

Volumn 49, Issue 7, 2008, Pages 1374-1383

  Neri, Antonino ^a,b   Marmiroli, Sandra ^c   Tassone, Pierfrancesco ^d   Lombardi, Luigia ^a   Nobili, Lucia ^b   Verdelli, Donata ^a   Civallero, Monica ^c   Cosenza, Maria ^c   Bertacchini, Jessika ^c   Federico, Massimo ^c   De Pol, Anto ^c   Deliliers, Giorgio Lambertenghi ^a,b   Sacchi, Stefano ^c  

^a IRCCS   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^d UNIVERSITY MAGNA GRAECIA OF CATANZARO   (Italy)

Author keywords

AKT; Apoptosis; Caspases; Enzastaurin; Multiple myeloma; Signal transduction pathways

Indexed keywords

BORTEZOMIB; ENZASTAURIN; GLYCOGEN SYNTHASE KINASE 3BETA; PROTEIN KINASE B; THALIDOMIDE;

APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DRUG POTENTIATION; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; MESENCHYME CELL; MULTIPLE MYELOMA; PRIORITY JOURNAL; STROMA CELL;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; CELL PROLIFERATION; HUMANS; INDOLES; INHIBITORY CONCENTRATION 50; MULTIPLE MYELOMA; PROTEIN KINASE C; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; STROMAL CELLS;

EID: 47649103741     PISSN: 10428194     EISSN: 10292403     Source Type: Journal    
DOI: 10.1080/10428190802078289     Document Type: Article

References (35)

1. Fonseca, R., Barlogie, B., Bataille, R., Bastard, C., Bergsagel, P. L. Chesi, M. et al. (2004) Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res, 64, pp. 1546-1558.
2. Ferlin, M., Noraz, N., Hertogh, C., Brochier, J., Taylor, N. and Klein, B. (2000) Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. Br J Haematol, 111, pp. 626-634.
3. Freund, G. G., Kulas, D. T. and Mooney, R. A. (1993) Insulin and IGF-1 increase mitogenesis and glucose metabolism in the multiple myeloma cell line, RPMI 8226. J Immunol, 151, pp. 1811-1820.
4. Klein, B., Zhang, X. G., Lu, Z. Y. and Bataille, R. (1995) Interleukin-6 in human multiple myeloma. Blood, 85, pp. 863-872.
5. Sirohi, B. and Powles, R. (2004) Multiple myeloma. Lancet, 363, pp. 875-887.
6. Richardson, P. G., Mitsiades, C. S., Hideshima, T. and Anderson, K. C. (2005) Novel biological therapies for the treatment of multiple myeloma. Best Pract Res Clin Haematol, 18, pp. 619-634.
7. van de Donk, N. W., Lokhorst, H. M. and Bloem, A. C. (2005) Growth factors and antiapoptotic signaling pathways in multiple myeloma. Leukemia, 19, pp. 2177-2185.
8. Goekjian, P. G. and Jirousek, M. R. (2001) Protein kinase C inhibitors as novel anticancer drugs. Expert Opin Invest Drugs, 10, pp. 2117-2140.
9. Shipp, M. A., Ross, K. N., Tamayo, P., Weng, A. P., Kutok, J. L. Aguiar, R. C. et al. (2002) Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med, 8, pp. 68-74.
10. Hans, C. P., Weisenburger, D. D., Greiner, T. C., Chan, W. C., Aoun, P. Cochran, G. T. et al. (2005) Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Mod Pathol, 18, pp. 1377-1384.
11. Graff, J. R., McNulty, A. M., Hanna, K. R., Konicek, B. W., Lynch, R. L. Bailey, S. N. et al. (2005) The protein kinase C beta 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, pp. 7462-7469.
12. Aeder, S. E., Martin, P. M., Soh, J. W. and Hussaini, I. M. (2004) PKC-beta mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene, 23, pp. 9062-9069.
13. Kawakami, Y., Nishimoto, H., Kitaura, J., Maeda-Yamamoto, M., Kato, R. M. Littman, D. R. et al. (2004) Protein kinase C betaII regulates Akt phosphorylation on Ser-473 in a cell type- and stimulus-specific fashion. J Biol Chem, 279, pp. 47720-47725.
14. Partovian, C. and Simons, M. (2004) Regulation of protein kinase B/Akt activity and Ser473 phosphorylation by protein kinase C alpha in endothelial cells. Cell Signal, 16, pp. 951-957.
15. Martelli, A. M., Nyakern, M., Tabellini, G., Bortul, R., Tazzari, P. L. Evangelisti, C. et al. (2006) Phosphoinositide 3-Kinase/AKT signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia, 20, pp. 911-928.
16. Miranda, M. B. and Johnson, D. E. (2007) Signal transduction pathways that contribute to myeloid differentiation. Leukemia, 21, pp. 1363-1377.
17. Nyakern, M., Tazzari, P. L., Finelli, C., Bosi, C., Follo, M. Y. Grafone, T. et al. (2006) Frequent elevation of AKT kinase phosphorilation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients. Leukemia, 20, pp. 230-238.
18. Papa, V., Tazzari, P. L., Cappellini, A., Cappellini, A., Ricci, F. Billi, A. M. et al. (2008) Proapoptotic activity and chemosensitizing effect of the novel AKT inhibitor perifosine in acute myelogenous leukemia cells. Leukemia, 22, pp. 147-160.
19. Hsu, J., Shi, Y., Krajewski, S., Renner, S., Fisher, M. Reed, J. C. et al. (2001) The AKT kinase is activated in multiple myeloma tumor cells. Blood, 98, pp. 2853-2855.
20. Tu, Y., Gardner, A. and Lichtenstein, A. (2000) The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: Roles in cytokine-dependent survival and proliferative responses. Cancer Res, 60, pp. 6763-6770.
21. Pene, F., Claessens, Y. E., Muller, O., Viguie, F., Mayeux, P. and Dreyfus, F. (2002) Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene, 21, pp. 6587-6597.
22. Keyes, K. A., Mann, L., Sherman, M., Galbreath, E., Schirtzinger, L. and Ballard, D. (2004) LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol, 53, pp. 133-140.
23. Teicher, B. A., Alvarez, E., Menon, K., Esterman, M. A., Considine, E. Shih, C. et al. (2002) Antiangiogenic effects of a protein kinase C beta-selective small molecule. Cancer Chemother Pharmacol, 49, pp. 69-77.
24. Querfeld, C., Rizvi, M. A., Kuzel, T. M., Guitart, J., Rademaker, A. Sabharwal, S. S. et al. (2006) The selective protein kinase C beta inhibitor enzastaurin induces apoptosis in cutaneous T-cell lymphoma cell lines through the AKT pathway. J Invest Dermatol, 126, pp. 1641-1647.
25. Rizvi, M. A., Ghias, K., Davies, K. M., Ma, C., Weinberg, F. Munshi, H. G. et al. (2006) Enzastaurin (LY317615), a protein kinase C beta inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines. Mol Cancer Ther, 5, pp. 1783-1789.
26. Podar, K., Raab, M. S., Zhang, J., McMillin, D., Breitkreutz, I. Tai, Y. T. et al. (2007) Targeting PKC in multiple myeloma: In vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl). Blood, 109, pp. 1669-1677.
27. Baumann, P., Armann, J., Mandl-Weber, S., Grun, G., Oduncu, F. and Schmidmaier, R. (2008) Inhibitors of protein kinase C sensitise multiple myeloma cells to common genotoxic drugs. Eur J Haematol, 80, pp. 37-45.
28. Verdelli, D., Mattioli, M., Fabris, S., Nobili, L., Intini, D. Guerneri, S. et al. (2005) Molecular and biological characterization of three novel interleukin-6-dependent human myeloma cell lines. Haematologica, 90, pp. 1541-1548.
29. Drexler, H. G. and Matsuo, Y. (2000) Malignant hematopoietic cell lines: in vitro models for the study of multiple myeloma and plasma cell leukemia. Leuk Res, 24, pp. 681-703.
30. Inoue, J., Otsuki, T., Hirasawa, A., Imoto, I., Matsuo, Y. Shimizu, S. et al. (2004) Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug resistance phenotype in multiple myeloma. Am J Pathol, 165, pp. 71-81.
31. Ronchetti, D., Greco, A., Compasso, S., Colombo, G., Dell'Era, P. Otsuki, T. et al. (2001) Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): Comparative analysis of Y373C, K650E and the novel G384D mutations. Oncogene, 20, pp. 3553-3562.
32. Chou, T. C. and Talalay, P. (1984) Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul, 22, pp. 27-55.
33. Chou, T. C. (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev, 58, pp. 621-681.
34. Moreau, A. S., Jia, X., Ngo, H. T., Leleu, X., O'Sullivan, G. Alsayed, Y. et al. (2007) Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstrom's Macroglobulinemia. Blood, 109, pp. 4964-4972.
35. Carducci, M. A., Musib, L., Kies, M. S., Pili, R., Truong, M. Brahmer, J. R. et al. (2006) 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, pp. 4092-4099.