Antitumor Activity of Bortezomib Alone and in Combination with Trail in Human Acute Myeloid Leukemia

Ruggero De Maria Marchiano, Concetta Conticello, Luana Adamo, Luisa Vicari, Raffaella Giuffrida, Gioacchin Iannolo, Gabriele Anastasi, Laura Caruso, Gaetano Moschetti, Alessandra Cupri, Giuseppe Antonio Palumbo, Massimo Gulisano, Rosario Giustolisi, Francesco Di Raimondo

Risultato della ricerca: Contributo in rivistaArticolo in rivista

25 Citazioni (Scopus)

Abstract

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60-70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 μM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy. Copyright © 2008 S. Karger AG.
Lingua originaleEnglish
pagine (da-a)19-30
Numero di pagine12
RivistaActa Haematologica
Volume120
DOI
Stato di pubblicazionePubblicato - 2008

Keywords

  • Acute myeloid leukemia
  • Antineoplastic Agents
  • Apoptosis
  • Boronic Acids
  • Bortezomib
  • Caspases
  • Cell Cycle Proteins
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Hematology
  • Humans
  • In Vitro Techniques
  • Leukemia, Myeloid, Acute
  • Male
  • Medicine (all)
  • Neoplasm Proteins
  • Protease Inhibitors
  • Pyrazines
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TRAIL

Fingerprint Entra nei temi di ricerca di 'Antitumor Activity of Bortezomib Alone and in Combination with Trail in Human Acute Myeloid Leukemia'. Insieme formano una fingerprint unica.

Cita questo