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Molecular Targets for Therapy

Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines

Leukemia volume 21, pages 421–426 (2007)Cite this article

Abstract

Imatinib mesylate is a selective inhibitor of the oncogenic tyrosine kinase, Bcr-Abl, and is widely used as a first-line treatment for chronic myeloid leukaemia (CML). Prolonged monotherapy is frequently associated with patients becoming refractory to imatinib. Therefore, there is considerable interest in small molecule inhibitors which may be used either as replacements or as adjuncts to existing imatinib therapy. For this purpose, it is most likely that drugs which do not share imatinib's mechanism of action will be most valuable. We compared two such compounds with different modes of action, adaphostin and 17-allylamino-17-demethoxygeldanamycin (17-AAG), for their cytotoxic effect and ability to induce the downregulation of cellular proteins in a murine haemopoietic cell line transformed with human p210Bcr-Abl, and two subclones resistant to imatinib owing to an Abl-kinase domain mutation (E255K) or amplification of the BCR-ABL gene, respectively. We found that, whereas 17-AAG selectively killed Bcr-Abl-positive cells and inhibited proteins dependent on heat-shock protein 90 for their stability (p210Bcr-Abl and Akt), adaphostin induced the downregulation of multiple cell-signalling proteins (p210Bcr-Abl, Akt, Bcr, Abl and STAT5a) and was cytotoxic to both Bcr-Abl-positive and -negative cells. We suggest that both compounds may prove useful in the treatment of CML but caution that undesirable side-effects may result from the inhibition of multiple cell signalling proteins.

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References

  1. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  PubMed  Google Scholar 

  2. Capdeville R, Buchdunger E, Zimmermann J, Matter A . Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002; 1: 493–502.

    Article  CAS  PubMed  Google Scholar 

  3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037.

    Article  CAS  PubMed  Google Scholar 

  4. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.

    Article  CAS  PubMed  Google Scholar 

  5. Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1423–1432.

    Article  CAS  PubMed  Google Scholar 

  6. Kantarjian HM, Cortes J, O'Brien S, Giles FJ, AlBitar M, Rios MB et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002; 99: 3547–3553.

    Article  CAS  PubMed  Google Scholar 

  7. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L . Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 2003; 4: 75–85.

    Article  PubMed  Google Scholar 

  8. Svingen PA, Tefferi A, Kottke TJ, Kaur G, Narayanan VL, Sausville EA et al. Effects of the bcr/abl kinase inhibitors AG957 and NSC 680410 on chronic myelogenous leukemia cells in vitro. Clin Cancer Res 2000; 6: 237–249.

    CAS  PubMed  Google Scholar 

  9. Schulte TW, Neckers LM . The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 1998; 42: 273–279.

    Article  CAS  PubMed  Google Scholar 

  10. Chandra J, Tracy J, Loegering D, Flatten K, Verstovsek S, Beran M et al. Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance. Blood 2006; 107: 2501–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li M, Wang H, Hill DL, Stinson S, Veley K, Grossi I et al. Preclinical pharmacology of the novel antitumor agent adaphostin, a tyrphostin analog that inhibits bcr/abl. Cancer Chemother Pharmacol 2006; 57: 607–614.

    Article  CAS  PubMed  Google Scholar 

  12. Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS et al. Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL – Inhibition of P-glycoprotein function by 17-AAG. Leukemia 2005; 19: 1198–1206.

    Article  CAS  PubMed  Google Scholar 

  13. Nimmanapalli R, O'Bryan E, Bhalla K . Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res 2001; 61: 1799–1804.

    CAS  PubMed  Google Scholar 

  14. Nimmanapalli R, O'Bryan E, Huang M, Bali P, Burnette PK, Loughran T et al. Molecular characterization and sensitivity of STI-571 (Imatinib Mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17- demethoxygeldanamycin. Cancer Res 2002; 62: 5761–5769.

    CAS  PubMed  Google Scholar 

  15. Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL . BCR-ABL point mutants isolated from patients with imatinib mesylate- resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat-shock protein 90. Blood 2002; 100: 3041–3044.

    Article  CAS  PubMed  Google Scholar 

  16. George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 2005; 105: 1768–1776.

    Article  CAS  PubMed  Google Scholar 

  17. Rahmani M, Reese E, Dai Y, Bauer C, Kramer LB, Huang M et al. Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change. Mol Pharmacol 2005; 67: 1166–1176.

    Article  CAS  PubMed  Google Scholar 

  18. Mow BM, Chandra J, Svingen PA, Hallgren CG, Weisberg E, Kottke TJ et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood 2002; 99: 664–671.

    Article  CAS  PubMed  Google Scholar 

  19. Chandra J, Hackbarth J, Le S, Loegering D, Bone N, Bruzek LM et al. Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells. Blood 2003; 102: 4512–4519.

    Article  CAS  PubMed  Google Scholar 

  20. Avramis IA, Christodoulopoulos G, Suzuki A, Laug WE, Gonzalez-Gomez I, McNamara G et al. In vitro and in vivo evaluations of the tyrosine kinase inhibitor NSC 680410 against human leukemia and glioblastoma cell lines. Cancer Chemother Pharmacol 2002; 50: 479–489.

    Article  CAS  PubMed  Google Scholar 

  21. Yu C, Rahmani M, Almenara J, Sausville EA, Dent P, Grant S . Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. Oncogene 2004; 23: 1364–1376.

    Article  CAS  PubMed  Google Scholar 

  22. Barnes DJ, Schultheis B, Adedeji S, Melo JV . Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia. Oncogene 2005; 24: 6432–6440.

    Article  CAS  PubMed  Google Scholar 

  23. Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res 2005; 65: 8912–8919.

    Article  CAS  PubMed  Google Scholar 

  24. Kabarowski JH, Allen PB, Wiedemann LM . A temperature sensitive p210 BCR-ABL mutant defines the primary consequences of BCR-ABL tyrosine kinase expression in growth factor dependent cells. EMBO J 1994; 13: 5887–5895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dasmahapatra G, Nguyen TK, Dent P, Grant S . Adaphostin and bortezomib induce oxidative injury and apoptosis in imatinib mesylate-resistant hematopoietic cells expressing mutant forms of Bcr/Abl. Leuk Res 2006; 30: 1263–1272.

    Article  CAS  PubMed  Google Scholar 

  26. Dasmahapatra G, Rahmani M, Dent P, Grant S . The tyrphostin adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells through a reactive oxygen species (ROS)-dependent mechanism. Blood 2006; 107: 232–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kaur G, Sausville EA . Altered physical state of p210bcr-abl in tyrphostin AG957-treated K562 cells. Anticancer Drugs 1996; 7: 815–824.

    Article  CAS  PubMed  Google Scholar 

  28. Orsolic N, Golemovic M, Quintas-Cardama A, Scappini B, Manshouri T, Chandra J et al. Adaphostin has significant and selective activity against chronic and acute myeloid leukemia cells. Cancer Sci 2006; 97: 952–960.

    Article  CAS  PubMed  Google Scholar 

  29. Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 2000; 275: 24273–24278.

    Article  CAS  PubMed  Google Scholar 

  30. Georgakis GV, Li Y, Rassidakis GZ, Martinez-Valdez H, Medeiros LJ, Younes A . Inhibition of heat-shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death. Clin Cancer Res 2006; 12: 584–590.

    Article  CAS  PubMed  Google Scholar 

  31. Topaly J, Schad M, Laufs S, Melo JV, Zeller WJ, Fruehauf S . Cross-resistance of imatinib mesylate and 17-AAG in imatinib-resistant cells that overexpress BCR-ABL. Br J Haematol 2003; 121: 672–673.

    Article  PubMed  Google Scholar 

  32. Ilaria Jr RL, Van Etten RA . P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 1996; 271: 31704–31710.

    Article  CAS  PubMed  Google Scholar 

  33. Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G et al. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood 1995; 86: 726–736.

    CAS  PubMed  Google Scholar 

  34. Ress A, Moelling K . Bcr is a negative regulator of the Wnt signalling pathway. EMBO R 2005; 6: 1095–1100.

    Article  CAS  Google Scholar 

  35. Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006; 20: 911–928.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Development Therapeutics Program of the National Cancer Institute, Bethesda, MD, USA, for their kind gifts of 17-AAG and adaphostin and Dr Elizabeth Buchdunger (Novartis Pharma) for imatinib. This work was supported by the Leukaemia Research Fund of Great Britain.

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  1. Department of Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK

    D J Barnes, S De, P van Hensbergen, È Moravcsik & J V Melo

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Correspondence to J V Melo.

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Barnes, D., De, S., van Hensbergen, P. et al. Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines. Leukemia 21, 421–426 (2007). https://doi.org/10.1038/sj.leu.2404533

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