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Anti-leukemic activity of Dasatinib in both p53wild-type and p53mutated B malignant cells

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Summary

The multi-kinase inhibitor Dasatinib induced a variable but significant decrease of viability in both p53wild-type (EHEB, JVM-2, JVM-3) and p53mutated (MEC-1, MEC-2, BJAB) prolymphocytic B leukemic cells, due to a combination of cell cycle block in G1 and apoptosis. Antibody phospho-kinase array analysis revealed that Dasatinib inhibited the phosphorylation of various kinases, including ERK1/2 and p38/MAPK as well as of STAT3 transcription factors, in both p53wild-type and p53mutated cells. Therefore, Dasatinib might offer a novel therapeutic strategy not only for p53wild-type, but also for p53mutated B malignancies that have the worst prognosis and urgently need innovative therapeutic approaches.

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References

  1. Talpaz M, Shah NP, Kantarjian H et al (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New Engl J Med 354:2531–2541

    Article  PubMed  CAS  Google Scholar 

  2. Amrein L, Hernandez TA, Ferrario C et al (2008) Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol 143:698–706

    Article  PubMed  CAS  Google Scholar 

  3. Veldurthy A, Patz M, Hagist S et al (2008) The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes. Blood 112:1443–1452

    Article  PubMed  CAS  Google Scholar 

  4. Secchiero P, Zerbinati C, di Iasio MG et al (2007) Synergistic cytotoxic activity of recombinant TRAIL plus the non-genotoxic activator of the p53 pathway nutlin-3 in acute myeloid leukemia cells. Curr Drug Metab 8:395–403

    Article  PubMed  CAS  Google Scholar 

  5. Secchiero P, Zerbinati C, Melloni E et al (2007) The MDM-2 antagonist Nutlin-3 promotes maturation of acute myeloid leukemic blasts. Neoplasia 9:853–861

    Article  PubMed  CAS  Google Scholar 

  6. Tavolaro S, Chiaretti S, Messina M et al (2010) Gene expression profile of protein kinases reveals a distinctive signature in chronic lymphocytic leukemia and in vitro experiments support a role of second generation protein kinase inhibitors. Leuk Res 34:733–741

    Article  PubMed  CAS  Google Scholar 

  7. Zenz T, Kröber A, Sherer K et al (2008) Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 112:3322–3329

    Article  PubMed  CAS  Google Scholar 

  8. Zauli G, Re MC, Furlini G, Giovannini M, La Placa M (1992) Human immunodeficiency virus type 1 envelope glycoprotein gp120-mediated killing of human haematopoietic progenitors (CD34+ cells). J Gen Virol 73:417–421

    Article  PubMed  CAS  Google Scholar 

  9. Secchiero P, Zerbinati C, Rimondi E et al (2004) TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells. Cell Mol Life Sci 61:1965–1974

    Article  PubMed  CAS  Google Scholar 

  10. Milani D, Zauli G, Rimondi E et al (2003) Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathways in SK-N-MC neuronal cells. J Neurochem 86:126–135

    Article  PubMed  CAS  Google Scholar 

  11. Milani D, Mazzoni M, Borgatti P, Zauli G, Cantley L, Capitani S (1996) Extracellular human immunodeficiency virus type-1 Tat protein activates phosphatidylinositol 3-kinase in PC12 neuronal cells. J Biol Chem 271:22961–22964

    Article  PubMed  CAS  Google Scholar 

  12. Demetri GD, Lo Russo P, MacPherson IRJ (2009) Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 15:6232–6240

    Article  PubMed  CAS  Google Scholar 

  13. Sainz-Perez A, Gary-Gouy H, Gaudin F et al (2008) IL-24 induces apoptosis of chronic lymphocytic leukemia B cells engaged into the cell cycle through dephosphorylation of STAT3 and stabilization of p53 expression. J Immunol 181:6051–6060

    PubMed  CAS  Google Scholar 

  14. Ghosh AK, Kay NE, Secreto CR, Shanafelt TD (2009) Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res 15:1250–1258

    Article  PubMed  CAS  Google Scholar 

  15. Mirandola P, Ponti C, Gobbi G et al (2004) Activated human NK and CD8+ T cells express both TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors, but are resistant to TRAIL-mediated cytotoxicity. Blood 104:2418–2424

    Article  PubMed  CAS  Google Scholar 

  16. Cheng JC, Kinjo K, Judelson DR et al (2008) CREB is a critical regulator of normal hematopoiesis and leukemogenesis. Blood 111:1182–1192

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the Italian Association for Cancer Research (AIRC) and CariFe Foundations. Federica Corallini is recipient of a FIRC fellowship.

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Authors and Affiliations

  1. Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100, Ferrara, Italy

    Raffaella Bosco, Rebecca Voltan, Federica Corallini, Silvano Capitani & Paola Secchiero

  2. Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy

    Marco Rabusin

  3. Department of Life Sciences, University of Trieste, Trieste, Italy

    Claudio Celeghini

Authors
  1. Raffaella Bosco
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  2. Marco Rabusin
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  3. Rebecca Voltan
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  4. Claudio Celeghini
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  5. Federica Corallini
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  6. Silvano Capitani
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  7. Paola Secchiero
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Corresponding author

Correspondence to Paola Secchiero.

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Bosco, R., Rabusin, M., Voltan, R. et al. Anti-leukemic activity of Dasatinib in both p53wild-type and p53mutated B malignant cells. Invest New Drugs 30, 417–422 (2012). https://doi.org/10.1007/s10637-010-9564-6

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  • DOI: https://doi.org/10.1007/s10637-010-9564-6

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