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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)19-30
Number of pages12
JournalActa Haematologica
Volume120
Issue number1
DOIs
Publication statusPublished - Oct 2008

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • Bortezomib
  • TRAIL

ASJC Scopus subject areas

  • Hematology

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