title: Tris (dibenzylideneacetone) dipalladium: a small-molecule palladium complex is effective in inducing apoptosis in chronic lymphocytic leukemia B-cells.
abstract: Here we tested impact of Tris (dibenzylideneacetone) dipalladium (Tris-DBA) on chronic lymphocytic leukemia (CLL) B-cell survival. Indeed, treatment of CLL B-cells with Tris-DBA induced apoptosis in a dose-dependent manner irrespective of IgVH mutational status. Further analyses suggest that Tris-DBA-induced apoptosis involves reduced expression of the anti-apoptotic proteins Bcl-xL, and XIAP with an upregulation of the pro-apoptotic protein BIM in CLL B-cells. Our findings also indicate that Tris-DBA targets the ribosomal protein (rp)-S6, an essential component of the Akt/mTOR signaling axis in CLL B-cells. Of interest, CLL bone marrow stromal cells were unable to protect the leukemic B cells from Tris-DBA-induced apoptosis in an in vitro co-culture system. Finally, co-administration of Tris-DBA and the purine nucleoside analog fludarabine (F-ara-A) augmented CLL B-cell apoptosis levels in vitro showing synergistic effects. In total, Tris-DBA is effective at inducing apoptosis in CLL B-cells even in the presence of stromal cells likely by targeting directly the signal mediator, rpS6.
authors.affiliation: a Division of Hematology , Mayo Clinic , Rochester , MN , USA ;
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: a Division of Hematology , Mayo Clinic , Rochester , MN , USA ;
authors.forename: Traci
authors.initials: T
authors.lastname: Sassoon
authors.affiliation: a Division of Hematology , Mayo Clinic , Rochester , MN , USA ;
authors.forename: Charla
authors.initials: C
authors.lastname: Secreto
authors.affiliation: a Division of Hematology , Mayo Clinic , Rochester , MN , USA ;
authors.forename: Sutapa
authors.initials: S
authors.lastname: Sinha
authors.affiliation: a Division of Hematology , Mayo Clinic , Rochester , MN , USA ;
authors.forename: Tait D
authors.initials: TD
authors.lastname: Shanafelt
authors.affiliation: b Stephenson Cancer Center, Department of Pathology , University of Oklahoma , Oklahoma , OK , USA ;
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: c Department of Dermatology , Emory University, Winship Cancer Institute , Atlanta , GA , USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D038601:Ribosomal Protein S6; C532099:tris(dibenzylideneacetone)dipalladium
keywords: CLL; Tris-DBA; fludarabine