Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells.
We have investigated the effect of combined treatment with CpG-oligodeoxynucleotide (CpG-ODN) plus Nutlin-3, a small molecule inhibitor of the murine double minute 2/p53 interaction, on the immune activation, cell cycle progression, and apoptosis of peripheral blood B chronic lymphocytic leukemia (B-CLL) cells. CpG-ODN induced a robust up-regulation of immune activation markers (CD54, CD69, CD80, CD86, MHC-II) in Zap70high and Zap70low B-CLL samples. Although cotreatment of B-CLL cells with CpG-ODN + Nutlin-3 did not interfere with such immune activation, CpG-ODN potentiated the Nutlin-3-mediated induction of the death receptors CD95 and TRAIL receptor 2. Importantly, treatment with CpG-ODN did not interfere with the ability of Nutlin-3 to inhibit cell cycle progression and to induce apoptosis. Thus, a therapeutic regimen including CpG-ODN plus Nutlin-3 might have the advantage to preserve the immune activation of B-CLL cells while restraining the prosurvival/proliferative potential of CpG-ODN treatment.
Secchiero
Paola
P
Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. secchier@mail.umbi.umd.edu
Melloni
Elisabetta
E
Tiribelli
Mario
M
Gonelli
Arianna
A
Zauli
Giorgio
G
D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006681:HLA-D Antigens / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis
D015703:Antigens, CD; C527702:CpG ODN 2395; D006681:HLA-D Antigens; D007093:Imidazoles; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D010879:Piperazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C482205:nutlin 3; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human