title: Phorbol ester-induced PKCepsilon down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation.
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.
authors.affiliation: Department of Anatomy, Pharmacology and Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, Parma, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Gobbi
authors.forename: Prisco
authors.initials: P
authors.lastname: Mirandola
authors.forename: Cecilia
authors.initials: C
authors.lastname: Carubbi
authors.forename: Cristina
authors.initials: C
authors.lastname: Micheloni
authors.forename: Chiara
authors.initials: C
authors.lastname: Malinverno
authors.forename: Paolo
authors.initials: P
authors.lastname: Lunghi
authors.forename: Antonio
authors.initials: A
authors.lastname: Bonati
authors.forename: Marco
authors.initials: M
authors.lastname: Vitale
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000008:administration & dosage / Q000494:pharmacology; D010703:Phorbol Esters / Q000008:administration & dosage / Q000494:pharmacology*; D051744:Protein Kinase C-epsilon / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D010703:Phorbol Esters; D053221:TNF-Related Apoptosis-Inducing Ligand; D015240:Phorbol 12,13-Dibutyrate; D051744:Protein Kinase C-epsilon; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8