Submitted March 6, 2008
Accepted October 24, 2008
Phorbol ester-induced PKC
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, and Marco Vitale*
Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Parma, Italy
Department of Clinical Sciences, University of Parma, Ospedale Maggiore, Parma, Italy
Department of Clinical Sciences University of Parma, Unit of Hematology, University Hospital of Parma, Parma, Italy
* Corresponding author; email: marco.vitale{at}unipr.it.
Despite the relevant therapeutic progresses made in these last two decades, the prognosis of acute myeloid leukaemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. 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 non-apoptotic functions, like cell differentiation. PKC
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 (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 PKC down-modulation, without affecting TRAIL receptors surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKC down-modulators) might represent a significative improvement of our therapeutic arsenal against AML.
