Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia

Acta Haematologica
Concetta ConticelloFrancesco Di Raimondo

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 microM 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 patien...Continue Reading

Citations

Jan 15, 2014·Cellular and Molecular Life Sciences : CMLS·Chiara GaspariniGiorgio Zauli
May 10, 2011·Expert Opinion on Therapeutic Targets·Giorgio ZauliPaola Secchiero
Sep 23, 2010·Expert Opinion on Therapeutic Targets·Massimo Breccia, Giuliana Alimena
Aug 3, 2010·Leukemia Research·Concetta ConticelloFrancesco Di Raimondo
Oct 13, 2009·Leukemia Research·Francesco Di Raimondo, Concetta Conticello
Apr 18, 2015·Frontiers in Oncology·Rachana Trivedi, Durga Prasad Mishra
Nov 10, 2009·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·John KorethLisbeth A Welniak
Dec 31, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Adel NaimiSaeed Solali

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