Skip to main content

Advertisement

SpringerLink
Log in

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The proteasome inhibitor bortezomib may be effective in combination with cytarabine and anthracyclines in the treatment of acute myeloid leukemia (AML) by virtue of targeting aberrantly activated NF-κB in AML stem cells. We tested whether bortezomib cytotoxicity is affected by multidrug resistance (MDR) proteins expressed in AML cells. We also tested whether bortezomib interactions with cytarabine and anthracyclines are affected by p53, because proteasome inhibition stabilizes p53 and may thus cause cell cycle arrest.

Experimental design

Bortezomib sensitivity of cell lines overexpressing P-glycoprotein, multidrug resistance protein-1, breast cancer resistance protein and lung resistance protein was studied in the presence and absence of established modulators of these transport proteins. Drug interactions during simultaneous and sequential exposure to bortezomib and anthracyclines or cytarabine in diverse ratios were evaluated by isobologram and combination index analyses in AML cell lines with wild type and inactive p53 and were correlated with cell cycle perturbations induced by bortezomib.

Results

Of the MDR mechanisms studied, only P-glycoprotein conferred resistance to bortezomib, and resistance was only twofold. Interactions between bortezomib and anthracylines and cytarabine changed from antagonistic to additive or synergistic with increasing drug activity levels and were not affected by p53 status.

Conclusions

MDR proteins and p53 do not affect bortezomib cytotoxicity or in vitro interactions with anthracyclines or cytarabine, but these interactions are concentration-dependent, and this concentration-dependency should be considered in the design of combination regimens.

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. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Ashikawa K, Shishodia S, Fokt I, Priebe W, Aggarwal BB (2004) Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues. Biochem Pharmacol 67:353–364

    Article  PubMed  CAS  Google Scholar 

  4. Attar EC, Learner E, Amrein PC (2004) In vitro studies of bortezomib with daunorubicin and cytarabine: sequence of administration affects leukemia cell chemosensitivity. Blood 104 [Abstract 4464]

  5. Baldwin AS (1996) The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14:649–681

    Article  PubMed  CAS  Google Scholar 

  6. Benderra Z, Faussat AM, Sayada L, Perrot JY, Chaoui D, Marie JP, Legrand O (2004) Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. Clin Cancer Res 10:7896–7902

    Article  PubMed  CAS  Google Scholar 

  7. Boccadoro M, Morgan G, Cavenagh J (2005) Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy. Cancer Cell Int 5:18

    Article  PubMed  Google Scholar 

  8. Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, Pazdur R (2004) Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 10:3954–3964

    Article  PubMed  CAS  Google Scholar 

  9. 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 

  10. Cortes J, Thomas D, Koller C, Giles F, Estey E, Faderl S, Garcia-Manero G, McConkey D, Ruiz SL, Guerciolini R, Wright J, Kantarjian H (2004) Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 10:3371–3376

    Article  PubMed  CAS  Google Scholar 

  11. Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61:3535–3540

    PubMed  CAS  Google Scholar 

  12. Frelin C, Imbert V, Griessinger E, Peyron AC, Rochet N, Philip P, Dageville C, Sirvent A, Hummelsberger M, Berard E, Dreano M, Sirvent N, Peyron JF (2005) Targeting NF-κB activation via pharmacological inhibition of IKK2 induced apoptosis of human acute myeloid leukemia cells. Blood 105:804–811

    Article  PubMed  CAS  Google Scholar 

  13. Gatto S, Scappini B, Pham L, Onida F, Milella M, Ball G, Ricci C, Divoky V, Verstovsek S, Kantarjian HM, Keating MJ, Cortes-Franco JE, Beran M (2003) The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate. Haematologica 88:853–863

    PubMed  CAS  Google Scholar 

  14. 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 50:18–27

    Google Scholar 

  15. Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Jordan CT (2001) Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98:2301–2307

    Article  PubMed  CAS  Google Scholar 

  16. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC (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 

  17. Horton TM, Gannavarapu A, Blaney SM, D’Argenio DZ, Plon SE, Berg S. (2006) Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol 58:13–23

    Article  PubMed  CAS  Google Scholar 

  18. Jung L, Holle L, Dalton WS (2004) Discovery, development, and clinical applications of bortezomib. Oncology 18(suppl 11):4–13

    PubMed  Google Scholar 

  19. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 18:621–663

    Article  PubMed  CAS  Google Scholar 

  20. Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaum FR, Willman CL (1997) Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group Study. Blood 89:3323–3329

    PubMed  CAS  Google Scholar 

  21. Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS, Head DR, Weick J, Grever MR, Appelbaum FR, Willman CL (1999) Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94:1086–1099

    PubMed  CAS  Google Scholar 

  22. Li ZR, Hromchak R, Mudipalli A, Bloch A (1998) Tumor suppressor proteins as regulators of cell differentiation. Cancer Res 58:4282–4287

    PubMed  CAS  Google Scholar 

  23. Ling YH, Liebes L, Jiang JD, Holland JF, Elliott PJ, Adams J, Muggia FM, Perez-Soler R (2003) Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res 9:1145–1154

    PubMed  CAS  Google Scholar 

  24. List AF, Spier CS, Grogan TM, Johnson C, Roe DJ, Greer JP, Wolff SN, Broxterman HJ, Scheffer GL, Scheper RJ, Dalton WS (1996) Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood 87:2464–2469

    PubMed  CAS  Google Scholar 

  25. Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, Wu ZQ, Borad MJ, Frantzen M, Rousos E, Neeser J, Mikail A, Adams J, Sjak-Shie N, Vescio RA, Berenson JR (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144

    PubMed  CAS  Google Scholar 

  26. MacLaren AP, Chapman RS, Wyllie AH, Watson CJ (2001) p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells. Cell Death Differ 8:210–218

    Article  PubMed  CAS  Google Scholar 

  27. Michaelis M, Fichtner I, Behrens D, Haider W, Rothweiler F, Mack A, Cinatl J, Doerr HW, Cinatl J Jr (2006) Anti-cancer effects of bortezomib against chemoresistant neuroblastoma cell lines in vitro and in vivo. Int J Oncol 28:439–446

    PubMed  CAS  Google Scholar 

  28. Minderman H, Suvannasankha A, O’Loughlin KL, Scheffer GL, Scheper RJ, Robey RW, Baer MR (2002) Flow cytometric analysis of breast cancer resistance protein expression and function. Cytometry 48:59–65

    Article  PubMed  CAS  Google Scholar 

  29. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380

    Article  PubMed  CAS  Google Scholar 

  30. Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, Pien CS, Millikan RE, Tu SM, Pagliaro L, Kim J, Adams J, Elliott P, Esseltine D, Petrusich A, Dieringer P, Perez C, Logothetis CJ (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 

  31. Qadir M, O’Loughlin K, Williamson NA, Fricke SM, Minderman H, Baer MR (2005) Cyclosporine A is a broad-spectrum multidrug resistance modulator. Clin Cancer Res 11:2320–2326

    Article  PubMed  CAS  Google Scholar 

  32. Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T (2005) MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 128:324–332

    Article  PubMed  CAS  Google Scholar 

  33. Shimizu T, Pommier Y (1997) Camptothecin-induced apoptosis in p53-null human leukemia HL60 cells and their isolated nuclei: effects of the protease inhibitors Z-VAD-fmk and dichloroisocoumarin suggest an involvement of both caspases and serine proteases. Leukemia 11:1238–1244

    Article  PubMed  CAS  Google Scholar 

  34. Sreenivasan Y, Sarkar A, Manna SK (2003) Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation. Oncogene 22:4356–4369

    Article  PubMed  CAS  Google Scholar 

  35. Vaziri SA, Hill J, Chikamori K, Grabowski DR, Takigawa N, Chawla-Sarkar M, Rybicki LR, Gudkov AV, Mekhail T, Bukowski RM, Ganapathi MK, Ganapathi R (2005) Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3 sigma and survivin. Mol Cancer Ther 4:1880–1890

    Article  PubMed  CAS  Google Scholar 

  36. Voorhees PM, Dees EC, O’Neil B, Orlowski RZ (2003) The proteasome as a target for cancer therapy. Clin Cancer Res 9:6316–6325

    PubMed  CAS  Google Scholar 

  37. Yanamandra N, Colaco NM, Parquet NA, Buzzeo RW, Boulware D, Wright G, Perez LE, Dalton WS, Beaupre DM (2006) Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin Cancer Res 12:591–599

    Article  PubMed  CAS  Google Scholar 

  38. Yin MB, Guo B, Vanhoefer U, Azrak RG, Minderman H, Frank C, Wrzosek C, Slocum HK, Rustum YM (2000) Characterization of protein kinase chk1 essential for the cell cycle checkpoint after exposure of human head and neck carcinoma A253 cells to a novel topoisomerase I inhibitor BNP1350. Mol Pharmacol 57:453–459

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a Leukemia and Lymphoma Society Translational Research Program Grant (to MRB), by shared resources of the Roswell Park Cancer Center Support Grant (P30 CA16056), the Leonard S. LoVullo Memorial Fund for Leukemia Research and the Dennis J. Szefel Jr. Endowed Fund for Leukemia Research at Roswell Park Cancer Institute.

Author information

Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Hans Minderman, Kieran L. O’Loughlin & Maria R. Baer

  2. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Yunfei Zhou

Authors
  1. Hans Minderman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunfei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kieran L. O’Loughlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria R. Baer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans Minderman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Minderman, H., Zhou, Y., O’Loughlin, K.L. et al. Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Cancer Chemother Pharmacol 60, 245–255 (2007). https://doi.org/10.1007/s00280-006-0367-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-006-0367-6

Keywords

Search

Navigation