Despite the relevant therapeutic progresses made in these last 2 decades, the prognosis of acute myeloid leukemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in turn, is a death ligand that spares normal cells and is therefore currently under clinical trials for cancer therapy. Emerging evidence, however, suggests that TRAIL is also involved in nonapoptotic functions, like cell differentiation. PKCÎµ is differentially modulated along normal hematopoiesis, and its levels modulate the response of hematopoietic precursors to TRAIL. Here, we investigated the effects of the combination of phorbol esters (phorbol ester 4-Î²- phorbol-12,13-dibutyrate [PDBu]) and TRAIL in the survival/differentiation of AML cells. We demonstrate here that PDBu sensitizes primary AML cells to both the apoptogenic and the differentiative effects of TRAIL via PKCÎµ down-modulation, without affecting TRAIL receptor surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKCÎµ down-modulators) might represent a significative improvement of our therapeutic arsenal against AML.
Phorbol ester-induced PKCÎµ down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation / G. Gobbi, P. Mirandola, C. Carubbi, C. Micheloni, C. Malinverno, P. Lunghi, A. Bonati, M. Vitale. - In: BLOOD. - ISSN 0006-4971. - 113:13(2009), pp. 3080-3087.
|Titolo:||Phorbol ester-induced PKCÎµ down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation|
|Parole Chiave:||Antineoplastic Agents; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 3; Caspase 8; Cell Culture Techniques; Cell Differentiation; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Leukemic; Humans; K562 Cells; Leukemia, Myeloid, Acute; Phorbol 12,13-Dibutyrate; Phorbol Esters; Protein Kinase C-epsilon; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Immunology; Biochemistry; Hematology; Cell Biology|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2009|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1182/blood-2008-03-143784|
|Appare nelle tipologie:||01 - Articolo su periodico|