Phorbol ester-induced PKCepsilon down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation

Giuliana Gobbi; Prisco Mirandola; Cecilia Carubbi; Cristina Micheloni; Chiara Malinverno; Paolo Lunghi; Antonio Bonati; Marco Vitale

doi:10.1182/blood-2008-03-143784

Phorbol ester-induced PKCepsilon down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation

Blood. 2009 Mar 26;113(13):3080-7. doi: 10.1182/blood-2008-03-143784. Epub 2008 Nov 6.

Authors

Giuliana Gobbi¹, Prisco Mirandola, Cecilia Carubbi, Cristina Micheloni, Chiara Malinverno, Paolo Lunghi, Antonio Bonati, Marco Vitale

Affiliation

¹ Department of Anatomy, Pharmacology and Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, Parma, Italy.

PMID: 18988868
DOI: 10.1182/blood-2008-03-143784

Abstract

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. PKCepsilon 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-beta-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 PKCepsilon down-modulation, without affecting TRAIL receptor surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKCepsilon down-modulators) might represent a significative improvement of our therapeutic arsenal against AML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects*
Apoptosis / genetics
CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Caspase 3 / genetics
Caspase 3 / metabolism
Caspase 8 / genetics
Caspase 8 / metabolism
Cell Culture Techniques
Cell Differentiation / drug effects*
Cell Differentiation / genetics
Down-Regulation / drug effects
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Drug Synergism
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Leukemic / drug effects
Humans
K562 Cells
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / enzymology
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Phorbol 12,13-Dibutyrate / administration & dosage
Phorbol 12,13-Dibutyrate / pharmacology
Phorbol Esters / administration & dosage
Phorbol Esters / pharmacology*
Protein Kinase C-epsilon / genetics*
Protein Kinase C-epsilon / metabolism
TNF-Related Apoptosis-Inducing Ligand / administration & dosage
TNF-Related Apoptosis-Inducing Ligand / pharmacology
TNF-Related Apoptosis-Inducing Ligand / therapeutic use*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
CASP8 and FADD-Like Apoptosis Regulating Protein
Phorbol Esters
TNF-Related Apoptosis-Inducing Ligand
Phorbol 12,13-Dibutyrate
Protein Kinase C-epsilon
CASP3 protein, human
CASP8 protein, human
Caspase 3
Caspase 8