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Bortezomib interactions with chemotherapy agents in acute leukemia in vitro

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Abstract

Although there is effective chemotherapy for many patients with leukemia, 20% of children and up to 65% of adults relapse. Novel therapies are needed to treat these patients. Leukemia cells are very sensitive to the proteasome inhibitor bortezomib (VELCADE®, PS-341), which enhances the in vitro cytotoxic effects of dexamethasone and doxorubicin in multiple myeloma. To determine if bortezomib enhances the cytotoxicity of agents used in leukemia, we employed an in vitro tetrazolium-based colorimetric assay (MTT) to evaluate the cytotoxic effects of bortezomib alone and in combination with dexamethasone, vincristine, doxorubicin, cytarabine, asparaginase, geldanamycin, trichostatin A, and the bcl-2 inhibitor HA14.1. We demonstrated that primary leukemia lymphoblasts and leukemia cell lines are sensitive to bortezomib, with an average IC50 of 12 nM. Qualitative and quantitative bortezomib-drug interactions were evaluated using the universal response surface approach (URSA). Bortezomib was synergistic with dexamethasone in dexamethasone-sensitive leukemia cells, and additive with vincristine, asparaginase, cytarabine, and doxorubicin. The anti-leukemic activity of bortezomib was also additive with geldanamycin and HA14.1, and additive or synergistic with trichostatin A. These results were compared to analysis using the median-dose effect method, which generated complex drug interactions due to differences in dose-response curve sigmoidicities. These data suggest bortezomib could potentiate the cytotoxic effects of combination chemotherapy in patients with leukemia.

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References

  1. SEER Cancer Statistic Review, 1973–1999 Bethesda, MD: National Cancer Institute, 2000;467–482

  2. Hochstrasser M (1995) Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol 7:215–223

    Article  PubMed  CAS  Google Scholar 

  3. Spataro V, Norbury C, Harris AL (1998) The ubiquitin-proteasome pathway in cancer. Br J Cancer 77:448–455

    PubMed  CAS  Google Scholar 

  4. Ciechanover A (1994) The ubiquitin-proteasome proteolytic pathway. Cell 79:13–21

    Article  PubMed  CAS  Google Scholar 

  5. Karin M, Cao Y, Greten FR et al (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310

    Article  PubMed  CAS  Google Scholar 

  6. Hideshima T, Chauhan D, Richardson P et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639–16647

    Article  PubMed  CAS  Google Scholar 

  7. Shinohara K, Tomioka M, Nakano H et al (1996) Apoptosis induction resulting from proteasome inhibition. Biochem J 317(Pt 2):385–388

    PubMed  CAS  Google Scholar 

  8. Drexler HC (1997) Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad.Sci USA 94:855–860

    Article  PubMed  CAS  Google Scholar 

  9. Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622

    PubMed  CAS  Google Scholar 

  10. Papandreou CN, Daliani DD, Nix D et al (2004) Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108–2121

    Article  PubMed  CAS  Google Scholar 

  11. Orlowski RZ, Stinchcombe TE, Mitchell BS et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420–4427

    Article  PubMed  CAS  Google Scholar 

  12. Masdehors P, Merle-Beral H, Magdelenat H et al (2000) Ubiquitin-proteasome system and increased sensitivity of B-CLL lymphocytes to apoptotic death activation. Leuk Lymphoma 38:499–504

    PubMed  CAS  Google Scholar 

  13. Hideshima T, Richardson P, Chauhan D et al (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076

    PubMed  CAS  Google Scholar 

  14. Soligo D, Servida F, Delia D et al (2001) The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. Br J Haematol 113:126–135

    Article  PubMed  CAS  Google Scholar 

  15. Mitsiades N, Mitsiades CS, Richardson PG et al (2002) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380

    Article  PubMed  Google Scholar 

  16. Pajonk F, Pajonk K, McBride WH (2000) Apoptosis and radiosensitization of Hodgkin cells by proteasome inhibition. Int J Radiat Oncol Biol Phys 47:1025–1032

    PubMed  CAS  Google Scholar 

  17. Dai Y, Rahmani M, Grant S (2003) Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 22:7108–7122

    Article  PubMed  CAS  Google Scholar 

  18. Dai Y, Rahmani M, Pei XY et al (2004) Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 104:509–518

    Article  PubMed  CAS  Google Scholar 

  19. Mitsiades CS, Mitsiades NS, McMullan CJ et al (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 101:540–545

    Article  PubMed  CAS  Google Scholar 

  20. Adachi M, Zhang Y, Zhao X et al (2004) Synergistic effect of histone deacetylase inhibitors FK228 and m-carboxycinnamic acid bis-hydroxamide with proteasome inhibitors PSI and PS-341 against gastrointestinal adenocarcinoma cells. Clin Cancer Res 10:3853–3862

    Article  PubMed  CAS  Google Scholar 

  21. Pei XY, Dai Y, Grant S (2003) The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 17:2036–2045

    Article  PubMed  CAS  Google Scholar 

  22. Wang CY, Mayo MW, Korneluk RG et al (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683

    Article  PubMed  CAS  Google Scholar 

  23. Wang CY, Cusack JC Jr, Liu R et al (1999) Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nature Medicine 5:412–417

    Article  PubMed  Google Scholar 

  24. Izban KF, Ergin M, Huang Q et al (2001) Characterization of NF-kappaB expression in Hodgkin’s disease: inhibition of constitutively expressed NF-kappaB results in spontaneous caspase-independent apoptosis in Hodgkin and Reed-Sternberg cells. Mod.Pathol 14:297–310

    Article  PubMed  CAS  Google Scholar 

  25. Richardson PG, Hideshima T, Mitsiades C et al (2004) Proteasome inhibition in hematologic malignancies. Ann Med 36:304–314

    Article  PubMed  CAS  Google Scholar 

  26. Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498

    Article  PubMed  CAS  Google Scholar 

  27. O’Connor OA, Wright J, Moskowitz C et al (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23:676–684

    Article  PubMed  CAS  Google Scholar 

  28. Goy A, Younes A, McLaughlin P et al (2005) Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23:667–675

    Article  PubMed  CAS  Google Scholar 

  29. An WG, Hwang SG, Trepel JB et al (2000) Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 14:1276–1283

    Article  PubMed  CAS  Google Scholar 

  30. Yu C, Rahmani M, Dent P et al (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295:555–566

    Article  PubMed  CAS  Google Scholar 

  31. Tan C, Waldmann TA (2002) Proteasome inhibitor PS-341, a potential therapeutic agent for adult T- cell leukemia. Cancer Res 62:1083–1086

    PubMed  CAS  Google Scholar 

  32. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  33. Carmichael J, DeGraff WG, Gazdar AF et al (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942

    PubMed  CAS  Google Scholar 

  34. Greco WR, Park HS, Rustum YM (1990) Application of a new approach for the quantitation of drug synergism to the combination of cis-diamminedichloroplatinum and 1-beta-D-arabinofuranosylcytosine. Cancer Res 50:5318–5327

    PubMed  CAS  Google Scholar 

  35. DiArgenio DZ, Schumitsky A (1997)ADAPT II Users guide: pharmacokinetic/pharmacodynamic systems analysis software. (4). Los Angeles, CA, Biomedical systems resource

  36. Chou T, Talalay C (1984) Quantitative analysis of dose effect relationship: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  PubMed  CAS  Google Scholar 

  37. Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617

    Article  PubMed  CAS  Google Scholar 

  38. Appleman LJ, Ryan DP, Clark JW, Eder JP, Fishman M, Cusack JC Jr, Fidias P, Supko JG, Guerciolini R, Esseltine D, Kashala O (2003) Phase I dose escalation study of bortezomib and gemcitabine safety and tolerability in patients with advanced solid tumors. Proc ASCO 22:A839

    Google Scholar 

  39. Cusack JC (2003) Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. Cancer Treat Rev 29(Suppl 1):21–31

    Article  PubMed  CAS  Google Scholar 

  40. Gatto S, Scappini B, Pham L et al (2003) The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in B positive cell lines sensitive and resistant to imatinib mesylate. Haematologica 88:853–863

    PubMed  CAS  Google Scholar 

  41. Yu C, Rahmani M, Conrad D et al (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102:3765–3774

    Article  PubMed  CAS  Google Scholar 

  42. An J, Sun Y, Fisher M et al (2004) Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia 18:1699–1704

    Article  PubMed  CAS  Google Scholar 

  43. Zheng B, Georgakis GV, Li Y et al (2004) Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors. Clin Cancer Res 10:3207–3215

    Article  PubMed  CAS  Google Scholar 

  44. Chauhan D, Li G, Auclair D et al (2004) 2-Methoxyestardiol and bortezomib/proteasome-inhibitor overcome dexamethasone-resistance in multiple myeloma cells by modulating Heat Shock Protein-27. Apoptosis 9:149–155

    Article  PubMed  CAS  Google Scholar 

  45. Brown RE, Bostrom B, Zhang PL (2004) Morphoproteomics and bortezomib/dexamethasone-induced response in relapsed acute lymphoblastic leukemia. Ann.Clin Lab Sci 34:203–205

    PubMed  Google Scholar 

  46. Webb JL (1963) effect of more than one inhibitor. Enzymes and metabolic inhibitors ed Vol 1; New York: Academic Press, 66-79-487-512

  47. Faessel HM, Slocum HK, Jackson RC et al (1998) Super in vitro synergy between inhibitors of dihydrofolate reductase and inhibitors of other folate-requiring enzymes: the critical role of polyglutamylation. Cancer Res 58:3036–3050

    PubMed  CAS  Google Scholar 

  48. Chou JH (1991) Quantitation of synergism and antagonism of two or more drugs by computerized analysis. Synergism and antagonism in chemotherapy pp 223–241

  49. Pei XY, Dai Y, Grant S (2004) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezmib and histone deacetylase inhibitors. Clin Cancer Res 10:3839–3852

    Article  PubMed  CAS  Google Scholar 

  50. Greco WR, Bravo G, Parsons JC (1995) The search for synergy: a critical review from a response surface perspective. Pharmacol Rev 47:331–385

    PubMed  CAS  Google Scholar 

  51. Berenbaum MC (1989) What is synergy? Pharmacol Rev 41:93–141

    PubMed  CAS  Google Scholar 

  52. Zoli W, Ricotti L, Tesei A et al (2001) In vitro preclinical models for a rational design of chemotherapy combinations in human tumors. Crit Rev Oncol Hematol 37:69–82

    Article  PubMed  CAS  Google Scholar 

  53. Chang TT, Chou TC (2000) Rational approach to the clinical protocol design for drug combinations: a review. Acta Paediatr Taiwan 41:294–302

    PubMed  CAS  Google Scholar 

  54. Bonvini P, Dalla RH, Vignes N et al (2004) Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma kinase induced by 17-allylamino-demethoxygeldanamycin: role of the co-chaperone carboxyl heat shock protein 70-interacting protein. Cancer Res 64:3256–3264

    Article  PubMed  CAS  Google Scholar 

  55. Richardson PG, Hideshima T, Mitsiades C et al (2004) Proteasome inhibition in hematologic malignancies. Ann Med 36:304–314

    Article  PubMed  CAS  Google Scholar 

  56. Blaney SM, Bernstein M, Neville K et al (2004) Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children’s Oncology Group study (ADVL0015). J Clin Oncol 22:4752–4757

    Article  Google Scholar 

  57. 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 

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Authors and Affiliations

  1. Texas Children’s Cancer Center/Baylor College of Medicine, 6621 Fannin, MC 3-3320, Houston, TX, 77030, USA

    Terzah M. Horton, Anurhadha Gannavarapu, Susan M. Blaney, Sharon E. Plon & Stacey L. Berg

  2. Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA

    David Z. D’Argenio

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  1. Terzah M. Horton
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  2. Anurhadha Gannavarapu
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Correspondence to Terzah M. Horton.

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Horton, T.M., Gannavarapu, A., Blaney, S.M. et al. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol 58, 13–23 (2006). https://doi.org/10.1007/s00280-005-0135-z

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