Skip to main content

Advertisement

SpringerLink
Log in

Combination of low doses of Enzastaurin and Lenalidomide has synergistic activity in B-non-Hodgkin lymphoma cell lines

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Less toxic and more active treatments are needed for indolent lymphomas as there is no curative treatment, and patients eventually die due to complications related to their disease. The purpose of the present study was to assess the antitumour activity of the combination of low doses of Enzastaurin and Lenalidomide (Revlimid) on B-lymphoma cell lines. The combination of Enzastaurin and Lenalidomide, at doses as low as 1 μM, showed strong synergism against indolent lymphomas by reducing cell growth, producing an increase in G0–G1 phase followed by significant decrease in S phase, increasing apoptosis, and inhibiting PI3K/AKT, PKC and MAPK/ERK pathways. These preclinical findings, together with promising results obtained with Lenalidomide for the treatment of non-Hodgkin lymphoma, suggest that further evaluation of the combination of Enzastaurin and Lenalidomide for the treatment of indolent lymphomas is warranted. These compounds, with a favourable toxicity profile, are not classic chemotherapeutic agents, causing severe side effects, and could be considered an example of a new innovative attempt of an anti-cancer ‘soft treatment’.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jaffe ES, Harris NL, Vardiman JW Stein H (2001) World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues, vol 352. IARC Press, Lyon, p 85

    Google Scholar 

  2. Luminari S, Cesaretti M, Rashid I, Mammi C, Montanini A, Barbolini E et al (2007) Incidence, clinical characteristics and survival of malignant lymphomas: a population-based study from a cancer registry in northern Italy. Hematol Oncol 25:189–197

    Article  PubMed  Google Scholar 

  3. Faul MM, Gillig JR, Jirousek MR, Ballas LM, Schotten T, Kahl A et al (2003) Acyclic N-(azacycloalkyl) bisindolylmaleimides: isozyme selective inhibitors of PKC-beta. Bioorg Med Chem Lett 13:1857–1859

    Article  PubMed  CAS  Google Scholar 

  4. Graff JR, McNulty AM, Hanna KR, Konicek BW, Lynch RL, Bailey SN 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 65:7462–7469

    Article  PubMed  CAS  Google Scholar 

  5. Querfeld C, Rizvi MA, Kuzel TM, Guitart J, Rademaker A, Sabharwal SS 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 126:1641–1647

    Article  PubMed  CAS  Google Scholar 

  6. Moreau AS, Jia X, Ngo HT, 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 macroglobulinemia. Blood 109:4964–4972

    Article  PubMed  CAS  Google Scholar 

  7. Podar K, Raab MS, Zhang J, McMillin D, Breitkreutz I, Tai YT 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 109:1669–1677

    Article  PubMed  CAS  Google Scholar 

  8. Morgillo F, Martinelli E, Troiani T, Laus G, Pepe S, Gridelli C et al (2008) Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase C beta inhibitor, in non-small cell lung cancer cells. Mol Cancer Ther 7:1698–1707

    Article  PubMed  CAS  Google Scholar 

  9. Lee KW, Kim SG, Kim HP, Kwon E, You J, Choi HJ et al (2008) Enzastaurin, a protein kinase C beta inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells. Cancer Res 68:1916–1926

    Article  PubMed  CAS  Google Scholar 

  10. Neri A, Marmiroli S, Tassone P, Lombardi L, Nobili L, Verdelli D et al (2008) The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines. Leuk Lymphoma 49:1374–1383

    Article  PubMed  CAS  Google Scholar 

  11. Civallero M, Cosenza M, Grisendi G, Marcheselli L, Todoerti K, Sacchi S (2010) Effects of enzastaurin, alone or in combination, on signaling pathway controlling growth and survival of B-cell lymphoma cell lines. Leuk Lymphoma 51:671–679

    Article  PubMed  CAS  Google Scholar 

  12. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F et al (2002) Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100:3063–3067

    Article  PubMed  CAS  Google Scholar 

  13. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al (2005) Efficacy of Lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549–557

    Article  PubMed  CAS  Google Scholar 

  14. Sher T, Miller KC, Lawrence D, Whitworth A, Hernandez-Ilizaliturri F, Czuczman MS et al (2010) Efficacy of Lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics. Leuk Lymphoma 51:85–88

    Article  PubMed  CAS  Google Scholar 

  15. Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S et al (2008) Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111:5291–5297

    Article  PubMed  CAS  Google Scholar 

  16. Sissung TM, Thordardottir S, Gardner ER, Figg WD (2009) Current status of thalidomide and CC-5013 in the treatment of metastatic prostate cancer. Anticancer Agents Med Chem 9:1058–1069

    Article  PubMed  CAS  Google Scholar 

  17. Amato RJ, Hernandez-McClain J, Saxena S, Khan M (2008) Lenalidomide therapy for metastatic renal cell carcinoma. Am J Clin Oncol 31:244–249

    PubMed  CAS  Google Scholar 

  18. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA et al (2007) Lenalidomide plus Dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142

    Article  PubMed  CAS  Google Scholar 

  19. List A, Gordon D, Bennett J, Giagounidis A, Raza A, Feldman E et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465

    Article  PubMed  CAS  Google Scholar 

  20. Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT et al (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943–2950

    PubMed  CAS  Google Scholar 

  21. Bartlett JB, Dredge K, Dalgleish AG (2004) The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4:314–322

    Article  PubMed  CAS  Google Scholar 

  22. Zhu D, Corral LG, Fleming YW, Stein B (2008) Immunomodulatory drugs Revlimid (Lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother 57:1849–1859

    Article  PubMed  CAS  Google Scholar 

  23. Verhelle D, Corral LG, Wong K, Mueller JH, Moutouh-de Parseval L, Jensen-Pergakes K et al (2007) Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 67:746–755

    Article  PubMed  CAS  Google Scholar 

  24. Gandhi AK, Kang J, Naziruddin S, Parton A, Schafer PH, Stirling DI (2006) Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly. Leuk Res 30:849–858

    Article  PubMed  CAS  Google Scholar 

  25. Gartner S, Kaplan HS (1980) Long-term culture of human bone marrow cells. Proc Natl Acad Sci U S A 77:4756–4759

    Article  PubMed  CAS  Google Scholar 

  26. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  PubMed  CAS  Google Scholar 

  27. Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681

    Article  PubMed  CAS  Google Scholar 

  28. Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP (2000) Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol Ther 87:227–253

    Article  PubMed  CAS  Google Scholar 

  29. Ocio EM, Mateos MV, Maiso P, Pandiella A, San-Miguel JF (2008) New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol 9:1157–1165

    Article  PubMed  CAS  Google Scholar 

  30. Hallek M, Eichhorst BF (2004) Chemotherapy combination treatment regimens with fludarabine in chronic lymphocytic leukemia. Hematol J 5:20–30

    Article  Google Scholar 

  31. Kyrgiou M, Salanti G, Pavlidis N, Paraskevaidis E, Ioannidis JP (2006) Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst 98:1655–1663

    Article  PubMed  CAS  Google Scholar 

  32. Mauri D, Polyzos NP, Salanti G, Pavlidis N, Ioannidis JP (2008) Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst 100:1780–1791

    Article  PubMed  CAS  Google Scholar 

  33. Srikanth M, Davies FE, Morgan GJ (2008) An update on drug combinations for treatment of myeloma. Expert Opin Investig Drugs 17:1–12

    Article  PubMed  CAS  Google Scholar 

  34. Carducci MA, Musib L, Kies MS, Pili R, Truong M, Brahmer JR 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 24:4092–4099

    Article  PubMed  CAS  Google Scholar 

  35. Robertson MJ, Kahl BS, Vose JM, de Vos S, Laughlin M, Flynn PJ et al (2007) Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 25:1741–1746

    Article  PubMed  CAS  Google Scholar 

  36. Morschhauser F, Seymour JF, Kluin-Nelemans HC, Grigg A, Wolf M, Pfreundschuh M et al (2008) A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann Oncol 19:247–253

    Article  PubMed  CAS  Google Scholar 

  37. Rademaker-Lakhai JM, Beerepoot LV, Mehra N, Radema SA, van Maanen R, Vermaat JS et al (2007) 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 13:4474–4481

    Article  PubMed  CAS  Google Scholar 

  38. Ivanov V, Tabouret E, Chuto G, Chetaille B, Fezoui H, Coso D et al (2010) Rituximab–Lenalidomide–dexamethasone induces complete and durable remission in relapsed refractory diffuse large B-cell non-Hodgkin lymphoma. Leuk Lymphoma 51(9):1758–1760

    Article  PubMed  CAS  Google Scholar 

  39. Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G et al (2009) Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol 27:5404–5409

    Article  PubMed  CAS  Google Scholar 

  40. Fowler NH, McLaughlin P, Hagemeister FB, Kwak LW, Fanale MA, Neelapu SS, et al (2010) Complete response rates with Lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin's lymphoma. J Clin Oncol 28; Abstract 8036

Download references

Acknowledgements

We are grateful to the Associazione Angela Serra per la Ricerca sul Cancro for financial support.

Author information

Authors and Affiliations

  1. Program of Innovative Therapies in Oncology and Haematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124, Modena, Italy

    Maria Cosenza, Monica Civallero, Giulia Grisendi, Luigi Marcheselli, Alessia Bari & Stefano Sacchi

  2. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi, 287 41124, Modena, Italy

    Erika Roat

Authors
  1. Maria Cosenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monica Civallero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giulia Grisendi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luigi Marcheselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erika Roat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessia Bari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefano Sacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefano Sacchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cosenza, M., Civallero, M., Grisendi, G. et al. Combination of low doses of Enzastaurin and Lenalidomide has synergistic activity in B-non-Hodgkin lymphoma cell lines. Ann Hematol 91, 1613–1622 (2012). https://doi.org/10.1007/s00277-012-1490-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-012-1490-6

Keywords

Search

Navigation