Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells.

Abstract	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.
Authors	Paola Secchiero, Elisabetta Melloni, Mario Tiribelli, Arianna Gonelli, Giorgio Zauli
Journal	Journal of leukocyte biology (J Leukoc Biol) Vol. 83 Issue 2 Pg. 434-7 (Feb 2008) ISSN: 0741-5400 [Print] England
PMID	17998303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antigens, CD CpG ODN 2395 HLA-D Antigens Imidazoles Neoplasm Proteins Oligodeoxyribonucleotides Piperazines Receptors, TNF-Related Apoptosis-Inducing Ligand nutlin 3 ZAP-70 Protein-Tyrosine Kinase ZAP70 protein, human
Topics	Aged Antigens, CD (biosynthesis, genetics) Cell Cycle (drug effects) Cell Division (drug effects) Drug Screening Assays, Antitumor Drug Synergism Female HLA-D Antigens (biosynthesis, genetics) Humans Imidazoles (administration & dosage, pharmacology) Leukemia, Lymphocytic, Chronic, B-Cell (pathology) Lymphocyte Activation (drug effects) Male Middle Aged Neoplasm Proteins (analysis) Oligodeoxyribonucleotides (pharmacology) Piperazines (administration & dosage, pharmacology) Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics) Tumor Cells, Cultured (drug effects) ZAP-70 Protein-Tyrosine Kinase (analysis)

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