Tris (dibenzylideneacetone) dipalladium: a small-molecule palladium complex is effective in inducing apoptosis in chronic lymphocytic leukemia B-cells

• Type of Material: Article
• Authors: Neil E. Kay, Mayo Clinic; Traci Sassoon, Mayo Clinic; Charla Secreto, Mayo Clinic; Sutapa Sinha, Mayo Clinic; Tait D. Shanafelt, Mayo Clinic; Ashish K. Ghosh, University of Oklahoma; Jack Arbiser, Emory University
• Language: English
• Date: 2016-05-17
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Informa UK Limited, trading as Taylor & Francis Group.
• Final Published Version (URL): http://dx.doi.org/10.3109/10428194.2016.1161186
• Title of Journal or Parent Work: Leukemia & Lymphoma
• ISSN: 1042-8194
• Volume: 57
• Issue: 10
• Start Page: 2409
• End Page: 2416
• Keywords: CLL CELLS; PROLIFERATION; Tris-DBA; PROMOTES; ANGIOGENIC SWITCH; CLL; KINASE; Science & Technology; Hematology; ACTIVATION; IN-VIVO; fludarabine; SIGNALING PATHWAY; INHIBITOR; Life Sciences & Biomedicine; RIBOSOMAL-PROTEIN S6; Oncology
• Research Categories: Health Sciences, General

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.